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Dan L. Van Dyke Mayo Clinic Cytogenetics Laboratory, 200 First St SW, Rochester MN 55905, USA; [email protected]

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Franck Viguié Service d'Histologie-Embryologie-Cytogénétique, Unité de Cytogénétique Onco-Hématologique, Hôpital Universitaire Necker-Enfants

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Table of contents

Gene Section

GSKIP (GSK3-beta interaction protein) 197 Christine Bellanné-Chantelot, Isabelle Plo

KNL1 (cancer susceptibility candidate 5) 200 Masato Takimoto, Jean-Loup Huret

ATG2B (Autophagy-related 2B) 205 Christine Bellanné-Chantelot, Isabelle Plo

Leukaemia Section

Primary mediastinal B-cell lymphoma (PMBL) 208 Luis Miguel Juárez Salcedo, Samir Dalia

t(2;11)(p21;q23) without KMT2A (MLL) rearrangement 210 Ana L. Ruano, Shashirekha Shetty

t(1;12)(p36;p13) ETV6/PRDM16 215 Francois P. Duhoux, Hélène A. Poirel

t(1;1)(p36;p36) PRDM16/SKI 218 Jean-Loup Huret

t(1;3)(p36;q21) PSMD2/PRDM16 ??? 220 Jean-Loup Huret

t(1;7)(p36;p12) IKZF1/PRDM16 223 Jean-Loup Huret

Case Report Section

A pediatric case of acute lymphoblastic leukemia with t(2;9)(q12;q34) (RANBP2/ABL1 fusion) 225 Marc De Braekeleer, Nadia Guéganic, Alexandra Schifferli, Joëlle Tchinda

Gene Section Short Communication

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(6) 197



GSKIP (GSK3-beta interaction protein) Christine Bellanné-Chantelot, Isabelle Plo

Département de Génétique, Hpitaux Universitaires Pitié-Salpétrière-Charles Foix, Paris (CBC);

INSERM UMR1170, Institut Gustave Roussy, Villejuif, (CBC, IP), France. christine.bellanne-

[email protected]; [email protected]

Published in Atlas Database: October 2016

Online updated version : http://AtlasGeneticsOncology.org/Genes/GSKIPID64074ch14q32.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68250/10-2016-GSKIPID64074ch14q32.pdf DOI: 10.4267/2042/68250

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2017 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract GSK3beta interaction protein (GSKIP) is a negative

regulator of GSK3B (GSK3 beta) which is a highly

conserved serine-threonine kinase involved in many

cellular processes including glycogen metabolism,

proliferation, differentiation, and development.

GSKIP directly interacts with GSK3B through its C-

terminal conserved GSK3B -binding domain (GID)

and negatively regulates GSK3B in the Wnt/ beta -

catenin signaling pathway. The overexpression of

GSKIP may result in the activation of the Wnt

pathway involved in hematopoietic stem cell

homeostasis and normal megakaryopoiesis and in

the development of leukemia stem cells in acute

myeloid leukemia (AML). In a mouse model,

GSK3B allelic deletion results in a myelodysplastic

syndrome that, when combined with GSK3A

deletion, leads to AML

The germline duplication of ATG2B and GSKIP,

both located in 14q32.2, predisposes to the

development of familial myeloproliferative

neoplasms with autosomal dominant inheritance, in

particular essential thrombocythemia progressing to

leukemia. Overexpression of ATG2B and GSKIP

enhances megakaryocyte progenitor differentiation

by increasing progenitor sensitivity to

thrombopoietin. Both genes cooperate with somatic

JAK2, MPL and CALR mutations and their

overexpression provides a growth advantage to

hematopoietic cells carrying these driver mutations

that may explain the familial aggregation and the

progression of essential thrombocythemia to

myelofibrosis and leukemia.

Keywords

GSKIP; Myeloproliferative neoplasms (MPN);

essential thrombocythemia; myelofibrosis;

leukemia; predisposition; ATG2B/GSKIP;

chromosome 14; CNV; autophagy; Wnt/beta-

catenin pathway

Identity

Other names: C14orf129

HGNC (Hugo): GSKIP

Location : 14q32.2

Location (base pair)

GSKIP starts at 96.831.073 and ends at 96.853.629

bp (according to hg19-Feb_2009)

Local order

centromere to telomere.

Note

cooperates with ATG2B, also located in 14q32.2 and

included in the 700 kb duplication

NC_000014.9:g.96.163.103_96.857.129dup (on

Assembly GRCh37)

DNA/RNA

Description The GSKIP gene consists of 2 non-coding exons and

2 exons, spanning a coding region of 3433 bp.

Transcription There are four transcripts that differ by their 5'UTR

and encode the same protein. The longest transcript

(NM_001271904) of the GSKIP gene has a total

GSKIP (GSK3-beta interaction protein) Bellanné-Chantelot C, Plo I


total length of 1050 nucleotides.

Pseudogene

Not yet identified.

Protein

Description

The protein encoded by the GSKIP gene is the

GSK3-beta interaction protein of 139 amino acids,

with a calculated molecular mass of 15.648 kDa.

Expression

Expression of GSKIP has been detected in various

normal human tissues (bone marrow, whole blood,

thymus, brain, heart, muscle, colon, kidney, liver,

lung, pancreas, thyroid, salivary and adrenal glands,

skin, ovary, uterus, placenta, prostate and testis). The

gene is overexpressed in bone, colon and rectum.

In hematopoietic cells, GSKIP is expressed in

CD34+ purified hematopoietic progenitors and

CD36+ erythroblasts or CD41+ megakaryocytes

derived from CD34+ progenitors cultured in vitro

(Saliba et al, 2016)

Localisation

GSKIP is localized in the cytoplasm and nucleus.

Function

GSKIP belongs to the family of A-kinase anchoring

proteins (AKAPs) that bind serine/threonine kinase

(PKA). These AKAPs proteins interact with the

regulatory domain of PKA and facilitate their

phosphorylation. GSKIP directly interacts with

GSK3B through its C-terminal conserved GSK3B-

binding domain (GID; amino acid 115-139) and

negatively regulates GSK3B in the Wnt/beta-catenin

signaling pathway (Chou et al, 2006). The

overexpression of GSKIP may mimic activation of

the Wnt pathway involved in hematopoietic stem

cell homeostasis and normal megakaryopoiesis (Li et

al, 2008) and in the development of leukemia stem

cells in AML (Wang. et al, 2010).

It has recently been shown in a mouse model that

Gsk3b allelic deletion results in a myelodysplastic

syndrome that, when combined with GSK3A

deletion, leads to AML (Guezguez et al, 2016).

Mutations

Germinal

A germline 14q32.2 head-to-tail duplication of 700

kb has been associated with familial myeloid

malignancies (Saliba et al , 2015). The germline

duplication includes the genes TCL1A, GSKIP,

ATG2B, BDKRB1, BDKRB2 and the first exon of

AK7. The overexpression of ATG2B and GSKIP

that are expressed in myeloid cells, enhances

hematopoietic progenitor differentiation,

particularly of megacaryocytes. The development of

myeloid malignancies required the cooperation of

both genes with the myeloproliferative neoplasms

(MPN) driver JAK2 Val617Phe mutation, MPL or

CALR mutations. The mechanism of cooperation

between ATG2B and GSKIP with MPN driver

mutations remains unknown.

The germline duplication with the same distal and

proximal breakpoints has only been identified in

MPN families originated from West Indies

(Martinique) suggesting a founder effect.

Implicated in

Familial myeloproliferative neoplasms (MPN)

Disease

Familial MPN originated from West-indies

(Martinique) and in particular, essential

thrombocythemia progressing to myelofibrosis

and/or acute myeloid leukemia and primary

myelofibrosis may be linked to ATG2B/GSKIP

germline duplication. The predisposition is highly

penetrant (80%) and is characterized by an earlier

age of MPN onset in comparison to sporadic cases

(41 years versus > 60 years). The spectrum of

acquired driver mutations (JAK2 Val617Phe, MPL and

CALR mutations) is similar to the spectrum of

mutations in sporadic MPN cases.

Prognosis

The percentage of transformation is close to 50% in

these familial MPN cases and is related to the

detection of mutations affecting epigenetic regulator

genes such as TET2 IDH1 or IDH2.

Acute myeloid leukemia (AML)

Disease

AML originated from West-indies (Martinique) may

be linked to ATG2B/GSKIP germline duplication.

Prognosis

The prognosis of the disease is also linked to the

detection of acquired mutations in TET2, IDH1 or in

IDH2. No TP53 mutation was found, contrary to

what was observed in AML evolving from MPN,

suggesting a different pathway for leukemic

transformation.

References Chou HY, Howng SL, Cheng TS, Hsiao YL, Lieu AS, Loh JK, Hwang SL, Lin CC, Hsu CM, Wang C, Lee CI, Lu PJ, Chou CK, Huang CY, Hong YR. GSKIP is homologous to the Axin GSK3beta interaction domain and functions as a negative regulator of GSK3beta. Biochemistry. 2006 Sep 26;45(38):11379-89

Guezguez B, Almakadi M, Benoit YD, Shapovalova Z, Rahmig S, Fiebig-Comyn A, Casado FL, Tanasijevic B, Bresolin S, Masetti R, Doble BW, Bhatia M. GSK3 Deficiencies in Hematopoietic Stem Cells Initiate Pre-neoplastic State that Is Predictive of Clinical Outcomes of

GSKIP (GSK3-beta interaction protein) Bellanné-Chantelot C, Plo I


Human Acute Leukemia. Cancer Cell. 2016 Jan 11;29(1):61-74

Li D, August S, Woulfe DS. GSK3beta is a negative regulator of platelet function and thrombosis. Blood. 2008 Apr 1;111(7):3522-30

Saliba J, Saint-Martin C, Di Stefano A, Lenglet G, Marty C, Keren B, Pasquier F, Valle VD, Secardin L, Leroy G, Mahfoudhi E, Grosjean S, Droin N, Diop M, Dessen P, Charrier S, Palazzo A, Merlevede J, Meniane JC, Delaunay-Darivon C, Fuseau P, Isnard F, Casadevall N, Solary E, Debili N, Bernard OA, Raslova H, Najman A, Vainchenker W, Bellanné-Chantelot C, Plo I. Germline

duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies. Nat Genet. 2015 Oct;47(10):1131-40

Wang Y, Krivtsov AV, Sinha AU, North TE, Goessling W, Feng Z, Zon LI, Armstrong SA. The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML. Science. 2010 Mar 26;327(5973):1650-3

This article should be referenced as such:

Bellanné-Chantelot C, Plo I. GSKIP (GSK3-beta interaction protein). Atlas Genet Cytogenet Oncol Haematol. 2017; 21(6):197-199.

Gene Section Review




KNL1 (cancer susceptibility candidate 5) Masato Takimoto, Jean-Loup Huret

Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.

[email protected] (MT); Genetics, Dept Medical Information, University of Poitiers, CHU

Poitiers Hospital, F-86021 Poitiers, France. [email protected] (JLH)


Online updated version : http://AtlasGeneticsOncology.org/Genes/AF15q14ID318.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68251/10-2016-AF15q14ID318.pdf DOI: 10.4267/2042/68251

This article is an update of : Takimoto M. CASC5 (cancer susceptibility candidate 5). Atlas Genet Cytogenet Oncol Haematol 2013;17(1) Takimoto M. CASC5 (Cancer Sensitibity Candidate 5). Atlas Genet Cytogenet Oncol Haematol 2007;11(1) Huret JL, Charrin C. AF15q14 (ALL1 fused gene from 15q14). Atlas Genet Cytogenet Oncol Haematol 2000;4(2)


Abstract

Review on KNL1, with data on DNA, on the protein

encoded, and where the gene is implicated.

Keywords

KNL1

Identity

Other names: CT29, CASC5, AF15Q14, D40,

PPP1R5, hKNL-1, hSpc105, AF15q14, KIAA1570

HGNC (Hugo): KNL1

Location: 15q15.1

DNA/RNA

Note

Whole genomic size is about 70 kbp, but consists of

27 exons.

Transcription

KNL1 mRNA expression is dominant in normal

human testis and slight expression are observed in

other organs, such as placenta. Analysis on cancer

cell lines, such as HeLa, gave single band with 8.5

kb. There is another alternative splicing site at the 5'

side of this gene that generates a short exon with 78

bp in cDNA. There are potential other alternative

splicing at cancer cell lines.

Analysis on testis mRNA shows two bands with size

of approximately 6 and 8,5 kb which are probably

derived from the two isoforms.

Protein

Description

Encodes 1833 amino acids and 2342 amino acids.

The KLN1 protein contains: conserved motifs,

which are the following: a (S/G)ILK motif (aa 25-

28), a RRVSF motif (aa 57-61), and, for BUB3

recognition, MELT repeats (aa 140-161, 308-329,

474-494, 562-582, 750-769, 859-882, 902-924, 940-

962, 1025-1044, 1073-1096, 1114-1136, 1152-

1174). The Bubs recognition KI motifs

KI(D/N)XXXF(L/I)XXLK, are KIDTTSFLANLK

(aa 202-213) for BUB1, and KIDFNDFIKRLK (aa

238-249) for BUB1B: (BUBR1); a nuclear

localization signal (aa 1789-1803); a coiled coil

region (aa 1942-2133) and the ZWINT (Zwint-1)

binding region (aa 1834 or 19811 for a smaller

region -2108); and RWD repeats (aa 2109- 2353)

With the NSL1 (hMis14)-binding region (aa 2109-

2316), according to Kiyomitsu et al., 2011, VEGA

checking, and SwissProt.

KNL1 (cancer susceptibility candidate 5) Takimoto M, Huret JL


Figure 1. Domain structure of KNL1 protein. Brown arrows indicate protein interactions, and blue arrows and line with T-shape indicate phosphorylation and dephosphorylation, respectively. MT :microtubules. KT : kinetochore.

Expression

KNL1 protein expressions with molecular weight of

approximately 250 kDa and 300 kDa are observed in

human testicular germ cells and cancer cell lines.

Localisation

In germ cell of testis, significant high expressions of

KNL1 protein are observed in nucleus of

spermatocytes and slightly in spermatogonia. It is

noteworthy that round spermatids express

significantly high KNL1 protein in their pre-

acrosome. As KNL1 protein has no hydrophobic

signal peptide in its amino terminus, it probably

localizes outer surface of pre-acrosome membrane of

spermatids inside of the cells..

In mitosis KNL1 protein is localized in kinetochore

in a human cancer cell line.

Function

KNL1 is a large of kinetochore protein, constituting

KMN (KNL1/ MIS12 complex/ NDC80 complex)

network. KMN network is the central hub of outer

kinetochore, not only connecting mitotic

chromosomes and spindles but also coordinating

microtubule-binding, chromosome congression and

spindle assembly checkpoint (SAC) signaling. There

are two microtubule binding activity in KMN

network, one in NDC80 and the other in KNL1.

KNL1 protein binds directly microtubule through its

far N-terminal region, consisting of 68 amino acids,

in vitro, and indirectly through the interactions with

MIS12 and NDC80 complexes at its C-terminus.

KNL1 depletion affects metaphase chromosome

congression. In C. elegans,

The depletion preclude metaphase chromosomal

congression, while in yeast, Drosophila and human

cells, the depletions show partial alignment

phenotypes, in which some chromosomes congress

to the equator but many chromosomes remain

stranded near the spindle poles. In the N-terminus of

KNL1 protein, AURKB (Aurora kinase B)

phosphorylates SILK and RVSF motifs, and then

disrupts the interaction between KNL1 and protein

phosphatase I (PP1), which also binds the motifs.

KNL1 augments Aurora B kinase activity that

phosphorylates outer kinetochore protein, such as

NDC80, resulting in reduction its microtubule-

binding activity. Protein phosphatase 2A ( PP2A) is

recruited by BUB1B (BubR1), one of SAC protein.

Both PP1 and PPA2 are suggested to counteract

Aurora B kinase activity. Especially, PP1 was shown

to stabilize microtubule attachments to kinetochores

probably through KNL1, while Aurora B kinase

destabilizes microtubule-binding by NDC80



phosphorylation as described. The destabilized

binding of KNL1 to microtubules is presumably

important for correcting and eliminating erroneous

kinetochore-microtubule attachment during SAC.

It is suggested that the bindings with microtubule

and with PP1 also play roles in SAC silencing.

Although their binding sites are in close proximity,

one of their bindings do not affect the other, and they

contribute independently to the silencing of SAC.

Two KI motifs, KI1 and KI2, localized in the N-

terminus, bind SAC protein, BUB1 and BUB1B,

respectively, through tetratricopeptide repeats

(TPRs) of the proteins, resulting into folding the

motifs into short alpha-helices. Although BUB1

fragment with mutation in KI-binding domain was

not able to bind to KNL1 in vitro, BUB1 and BUB1B

mutants with KI-binding sites were able to attach to

kinetochore. Mutations in the BUB3-binding domain

(BUB3-BD) in BUB1 and BUB1B prevent

kinetochore localization of the SAC protein. BUB1

fragment consisting only of N-terminus with TPRs

does not localize to kinetochore and longer

fragments that accommodate BUB3-BD did. Those

results suggest that BUB3-BD of BUB1 and

BUB1B, rather than TPRs, is critical for their

recruitment to kinetochore and that the interaction

between TPRs of Bub proteins and KI-motif of

KNL1 might play a subsidiary role in the localization

of BUB1 and BUB1B to kinetochore. In response to

SAC signal, the first step of this response is

phosphorylation of MELT motifs of KNL1, located

in the N-terminal and central region, by Mps1

kinase, and then the phosphorylated MELT motifs

bind BUB3/BUB1complex, mediating SAC

signaling. KNL1- BUB3-BUB1(KBB) complex

binds MXD1 (MAD1)/ MAD2L1 (MAD2) complex,

and then, together with MAD1 phosphorylation by

Msp1, the binding leads to CDC20/MAD2

formation, an essential part of Mitotic Checkpoint

Complex (MCC) that inhibits Anaphase Promoting

Complex/Cyclosome (APC/C).

Recently, it suggested that there are two pathways

for recruiting MAD1-MAD2 that results in SAC

activation. One is the pathway through KBB, as

described above, the other is KNTC1 (ROD)-RW10-

ZWILCH, (RZZ) complex, which interacts with

KNL1 through ZWINT (Zwint-1 protein). The

former is required for SAC activation when

kinetochores are misaligned but is not essential when

kinetochores are unattached from microtubules. The

latter binds SPDL1 (Spindly protein) and MAD1-

MAD2, and causes the anaphase-onset delay in

response to unattached kinetochore independently of

the former.

It was suggested that the binding of KNL1 with

microtubules and with PP1 contribute to silencing of

SAC, in which motor protein dynein, moving along

on microtubules, is suggested to work to strip

MAD1-MAD2. The C-terminal region of KNL1

interacts with MIS12 and Zwint-1 protein, through

RWD motif and coiled-coiled region, respectively.

The binding with the former plays role in connecting

inner kinetochore with KNL1 and the latter mediates

the interaction of KNL1 with RZZ complex which

works in SAC regulation as described above.

Implicated in

Leukemia

A small subset of leukemia with a t(11;15)(q23;q14)

has been described for long and has often be referred

as: t(11;15)(q23;q15) MLL/AF15q14. KMT2A,

(previous symbol: mixed leukemia gene (MLL)) is

translocated with KNL1 (previous symbol CASC5,

originally described as AF15q14), which makes

research of published cases often arduous.

t(11;15)(q23;q15) and/or KMT2A/KNL1

t(11;15)(q23;q14-15) Data on 16 cases with a t(11;15)(q23;q14-15),

according to (Yang et al., 2014) are the following:

there was 2 of myelodysplastic syndrome (MDS)

cases, 10 acute myeloid leukemia (AML) cases (2

M1, 4 M2, 3 M4, and 1 NOS), and 4 acute

lymphoblastic leukemia (ALL) cases. Mean age of

the patients was 20.6 years (range 1-54); there were

11 males and 5 females. Abnormalities of

chromosome 3 were seen in 10 out of 16 cases. Out

of 8 patients for whom clinical data were available,

only 3 are in complete remission, whereas 5 patients

died with a mean survival period of 10.4 months.

t(11;15)(q23;q15) and KMT2A/KNL1 Of 7 cases with a t(11;15)(q23;q15) and

KMT2A/KNL1 hybrid gene and fusion protein

((Chinwalla et al., 2003; Kuefer et al., 2003; Meyer

et al., 2006; Yang et al., 2014). Diagnosis was:

therapy related MDS (t-MDS) in 2 cases, AML in 4

cases (1 M2, 2 AML-M4, 1 AML-NOS), and 1 de

novo T-ALL. Sex ratio was 5M:1F; There was 3

children and 4 adult patients. Of three cases with data

on survival, patients died at: 8 mths, 8 mths, and 22

mths. Of four cases with documented karyotypes: the

karyotype was a complex karyotype with markers in

two cases, abnormalities of chromosome 3 were seen

in three cases, +21 in two cases. KMT2A (MLL)

exon 8, 9, or 10 were fused to exon 10, 11 or 12 of

KNL1, the fusion protein contains the 1362 or 1418

first aa from MLL with aa 1796, 1818 or 1819 from

KNL1 (according to authors and/or VEGA).

A t(3;15;p14;q15) KNL1/ ADAMTS9-AS2 is

mentioned, without further data in the ChiTARS

database (Gorohovski et al., 2016) as a chimeric EST

(dbEST Id:12413828; accession BQ375909).

Lung cancer

In one study on primary lung cancer, KNL1 mRNA

expression was observed in more than 40% of the

cases, which is the highest among all the different

types of cancers examined. The study also revealed



that clinicopathological findings correlates with

KNL1 expression. KNL1 mRNA expression is more

frequent in the tumors with low differentiation than

the ones with moderate and high differentiation.

Further, the tumors derived from smoker express

higher incidence of KNL1 mRNA than the ones from

non-smoker.

Spermatogenesis

KNL1 mRNA was highly expressed in normal testis.

As KNL1 protein expressions were observed in

spermatogonia and spermatocytes in seminiferous

tube of human testes, this protein may also play a

role in cell division as a kinetochore protein in

meiotic cells. It is noteworthy that KNL1 protein is

also significantly expressed in pre-acrosome of

spermatids, especially from its early stage,

suggesting that KNL1 might be playing important

role in the formation of acrosome, an essential

organelle for fertilization. KNL1 expressions in

testes of the patients with infertility were

significantly lower than normal ones.

Microcephaly

Disease

Autosomal recessive primary microcephaly

(MCPH) is a very rare neuro-developmental disorder

with brain size reduction, no structural malformation

of the brain at birth, mild-to moderate mental

retardation and absence of other neurological or

somatic disease.

There are 12 genetic loci responsible for MCPH, and

it was suggested that one of the responsible genetic

locus, MCPH4, resides on chromosome 15.

Subsequently, the study on the patients with MCPH4

of consanguineous families in Morocco revealed that

a homozygous missense mutation was observed in

exon 18 of KNL1 gene.

This point mutation caused skipping this exon in

splicing reaction in the mRNA maturation of KNL1,

suggesting that the affected nucleotide is a part of

Exonic splicing enhancers.

The mutation resulted in frame-shift and truncation

of KNL1 protein.

As RWD repeats at near its carboxy terminus were

deleted by this mutation, the truncated protein is no

longer able to bind to Mis12, leading to the defected

recruitment of KNL1 protein to kinetochore. One of

the patients in the Morroco families has

cryptorchidism in addition to microcephaly. The

results of studies on MCH4 is a direct demonstration

that KNL1 is essential to cell division in vivo.

References Blencowe BJ. Exonic splicing enhancers: mechanism of action, diversity and role in human genetic diseases. Trends Biochem Sci. 2000 Mar;25(3):106-10

Bollen M. Kinetochore signalling: the KIss that MELTs Knl1. Curr Biol. 2014 Jan 20;24(2):R68-70

Caldas GV, DeLuca JG. KNL1: bringing order to the kinetochore. Chromosoma. 2014 Jun;123(3):169-81

Cheeseman IM, Chappie JS, Wilson-Kubalek EM, Desai A. The conserved KMN network constitutes the core microtubule-binding site of the kinetochore. Cell. 2006 Dec 1;127(5):983-97

Chinwalla V, Chien A, Odero M, Neilly MB, Zeleznik-Le NJ, Rowley JD. A t(11;15) fuses MLL to two different genes, AF15q14 and a novel gene MPFYVE on chromosome 15. Oncogene. 2003 Mar 6;22(9):1400-10

Espeut J, Cheerambathur DK, Krenning L, Oegema K, Desai A. Microtubule binding by KNL-1 contributes to spindle checkpoint silencing at the kinetochore. J Cell Biol. 2012 Feb 20;196(4):469-82

Faesen AC, Musacchio A. The (phospho) needle in the (MELT) Haystack. Mol Cell. 2015 Mar 5;57(5):765-6

Genin A, Desir J, Lambert N, Biervliet M, Van Der Aa N, Pierquin G, Killian A, Tosi M, Urbina M, Lefort A, Libert F, Pirson I, Abramowicz M. Kinetochore KMN network gene CASC5 mutated in primary microcephaly. Hum Mol Genet. 2012 Dec 15;21(24):5306-17

Gorohovski A, Tagore S, Palande V, Malka A, Raviv-Shay D, Frenkel-Morgenstern M. ChiTaRS-3.1-the enhanced chimeric transcripts and RNA-seq database matched with protein-protein interactions. Nucleic Acids Res. 2017 Jan 4;45(D1):D790-D795

Hayette S, Tigaud I, Vanier A, Martel S, Corbo L, Charrin C, Beillard E, Deleage G, Magaud JP, Rimokh R. AF15q14, a novel partner gene fused to the MLL gene in an acute myeloid leukaemia with a t(11;15)(q23;q14). Oncogene. 2000 Sep 7;19(38):4446-50

Jamieson CR, Govaerts C, Abramowicz MJ. Primary autosomal recessive microcephaly: homozygosity mapping of MCPH4 to chromosome 15. Am J Hum Genet. 1999 Nov;65(5):1465-9

Kerres A, Vietmeier-Decker C, Ortiz J, Karig I, Beuter C, Hegemann J, Lechner J, Fleig U. The fission yeast kinetochore component Spc7 associates with the EB1 family member Mal3 and is required for kinetochore-spindle association. Mol Biol Cell. 2004 Dec;15(12):5255-67

Kiyomitsu T, Murakami H, Yanagida M. Protein interaction domain mapping of human kinetochore protein Blinkin reveals a consensus motif for binding of spindle assembly checkpoint proteins Bub1 and BubR1. Mol Cell Biol. 2011 Mar;31(5):998-1011

Kops GJ, Saurin AT, Meraldi P. Finding the middle ground: how kinetochores power chromosome congression. Cell Mol Life Sci. 2010 Jul;67(13):2145-61

Krenn V, Wehenkel A, Li X, Santaguida S, Musacchio A. Structural analysis reveals features of the spindle checkpoint kinase Bub1-kinetochore subunit Knl1 interaction. J Cell Biol. 2012 Feb 20;196(4):451-67

Kuefer MU, Chinwalla V, Zeleznik-Le NJ, Behm FG, Naeve CW, Rakestraw KM, Mukatira ST, Raimondi SC, Morris

SW. Characterization of the MLL partner gene AF15q14 involved in t(11;15)(q23;q14). Oncogene. 2003 Mar 6;22(9):1418-24

Liu D, Vleugel M, Backer CB, Hori T, Fukagawa T, Cheeseman IM, Lampson MA. Regulated targeting of protein phosphatase 1 to the outer kinetochore by KNL1 opposes Aurora B kinase. J Cell Biol. 2010 Mar 22;188(6):809-20



Meyer C, Schneider B, Jakob S, Strehl S, Attarbaschi A, Schnittger S, Schoch C, Jansen MW, van Dongen JJ, den Boer ML, Pieters R, Ennas MG, Angelucci E, Koehl U, Greil J, Griesinger F, Zur Stadt U, Eckert C, Szczepański T, Niggli FK, Schäfer BW, Kempski H, Brady HJ, Zuna J, Trka J, Nigro LL, Biondi A, Delabesse E, Macintyre E, Stanulla M, Schrappe M, Haas OA, Burmeister T, Dingermann T, Klingebiel T, Marschalek R. The MLL recombinome of acute leukemias. Leukemia. 2006 May;20(5):777-84

Obuse C, Iwasaki O, Kiyomitsu T, Goshima G, Toyoda Y, Yanagida M. A conserved Mis12 centromere complex is linked to heterochromatic HP1 and outer kinetochore protein Zwint-1. Nat Cell Biol. 2004 Nov;6(11):1135-41

Przewloka MR, Zhang W, Costa P, Archambault V, D'Avino PP, Lilley KS, Laue ED, McAinsh AD, Glover DM. Molecular analysis of core kinetochore composition and assembly in Drosophila melanogaster. PLoS One. 2007 May 30;2(5):e478

Sasao T, Itoh N, Takano H, Watanabe S, Wei G, Tsukamoto T, Kuzumaki N, Takimoto M. The protein encoded by cancer/testis gene D40/AF15q14 is localized in spermatocytes, acrosomes of spermatids and ejaculated spermatozoa. Reproduction. 2004 Dec;128(6):709-16

Sasao T, Takimoto M, Itoh N, Maeda T, Tanaka T, Masumori N, Tsukamoto T. Testis cancer gene D40 expression and its relationship with clinicopathological features in infertile men. Int J Urol. 2011 Feb;18(2):175-9

Silió V, McAinsh AD, Millar JB. KNL1-Bubs and RZZ

Provide Two Separable Pathways for Checkpoint Activation at Human Kinetochores. Dev Cell. 2015 Dec 7;35(5):600-13

Simpson AJ, Caballero OL, Jungbluth A, Chen YT, Old LJ. Cancer/testis antigens, gametogenesis and cancer. Nat Rev Cancer. 2005 Aug;5(8):615-25

Takimoto M, Wei G, Dosaka-Akita H, Mao P, Kondo S, Sakuragi N, Chiba I, Miura T, Itoh N, Sasao T, Koya RC, Tsukamoto T, Fujimoto S, Katoh H, Kuzumaki N. Frequent expression of new cancer/testis gene D40/AF15q14 in lung cancers of smokers. Br J Cancer. 2002 Jun 5;86(11):1757-62

Taylor SS, Hussein D, Wang Y, Elderkin S, Morrow CJ. Kinetochore localisation and phosphorylation of the mitotic checkpoint components Bub1 and BubR1 are differentially regulated by spindle events in human cells. J Cell Sci. 2001 Dec;114(Pt 24):4385-95

Wei G, Takimoto M, Yoshida I, Mao PZ, Koya RC, Miura T, Kuzumaki N. Chromosomal assignment of a novel human gene D40. Nucleic Acids Symp Ser. 1999;(42):71-2

Welburn JP, Vleugel M, Liu D, Yates JR 3rd, Lampson MA, Fukagawa T, Cheeseman IM. Aurora B phosphorylates spatially distinct targets to differentially regulate the kinetochore-microtubule interface. Mol Cell. 2010 May 14;38(3):383-92

Yang JJ, Park TS, Lee ST, Seo JY, Oh SH, Cho EH, Strehl S, Mühlegger N, Dworzak MN, Zuna J, Pospisilova D, Meyer C, Marschalek R, Kim HJ, Kim SH. Molecular characterization and clinical impact of t(11;15)(q23;q14-15) MLL-CASC5 rearrangement. Haematologica. 2014 Jan;99(1):e11-3


Takimoto M, Huret JL. KNL1 (cancer susceptibility candidate 5). Atlas Genet Cytogenet Oncol Haematol. 2017; 21(6):200-204.

Gene Section Short Communication




ATG2B (Autophagy-related 2B) Christine Bellanné-Chantelot, Isabelle Plo

Département de Génétique, Hôpitaux Universitaires Pitié-Salpétrière-Charles Foix, Paris (CBC);

INSERM UMR1170, Institut Gustave Roussy, Villejuif, (CBC, IP), France. christine.bellanne-

[email protected]; [email protected]


Online updated version : http://AtlasGeneticsOncology.org/Genes/ATG2BID55326ch14q32.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68252/10-2016-ATG2BID55326ch14q32.pdf DOI: 10.4267/2042/68252


Abstract Autophagy is a cellular process involved in the

sequestration of cytosolic components and their

degradation by lysosomes. Autophagy has been

involved in physiological responses to stress or

aging and in the development of many human

diseases including solid and haematological cancers.

In humans, 16 autophagy-related genes are known.

The ATG2B protein is involved in the late steps of

the autophagy process i.e. the formation of

autophagosomes that fuse with lysosomes before

degradation. Loss-of -function (frameshift) acquired

mutations of ATG2B have been identified in gastric

and colorectal carcinomas with high microsatellite

instability. Both pharmacologic and genetic

evidence indicate that autophagy plays pleiotropic

functions in hematopoietic cell homeostasis and

leukemogeneis. Autophagy could exert two opposite

roles (cell death and survival) depending on the

nature of the hematopoietic malignancy.

The germline duplication of ATG2B and GSKIP,

both located in 14q32.2, predisposes to the

development of familial myeloproliferative

neoplasms with autosomal dominant inheritance, in

particular essential thrombocythemia progressing to

leukemia. Overexpression of ATG2B and GSKIP

enhances megakaryocyte progenitor differentiation

by increasing progenitor sensitivity to

thrombopoietin. Both genes cooperate with somatic

JAK2, MPL and CALR mutations and their

overexpression provides a growth advantage to

hematopoietic cells carrying these driver mutations

that may explain the familial aggregation and the

progression of essential thrombocythemia to

myelofibrosis and leukemia.

Keywords

ATG2B; Myeloproliferative neoplasms (MPN);

essential thrombocythemia; myelofibrosis;

leukemia; predisposition; ATG2B/GSKIP;

chromosome 14; CNV; autophagy; Wnt/beta-

catenin pathway

Identity

Other names: C14orf103

HGNC (Hugo): ATG2B

Location : 14q32.2

Location (base pair)

ATG2B starts at 96.745.539 and ends at 96.829.738

bp (on Assembly GRCh37)

Local order

telomere to centromere.

Note

cooperates with GSKIP, also located in 14q32.2 and

included in the 700 kb duplication

NC_000014.9:g.96.163.103_96.857.129dup (on

Assembly GRCh37)

DNA/RNA

Description

The ATG2B gene consists of 42 exons spanning a

region of 82.08 kb.

ATG2B (Autophagy-related 2B) Bellanné-Chantelot C, Plo I


Transcription

A single mRNA transcript (NM_018036.6) of the

ATG2B gene, with a total length of 6234

nucleotides, has been annotated.

Pseudogene

Not yet identified.

Protein

Description

The protein encoded by the ATG2B gene is the

autophagy-related protein 2 homolog B of 2078

amino acids, with a calculated molecular mass of

232.8 kDa

Expression

Expression of ATG2B has been detected in various

normal human tissues (bone marrow, whole blood,

thymus, brain, heart, muscle, colon, kidney, liver,

lung, pancreas, thyroid, salivary and adrenal glands,

skin, ovary, uterus, placenta, prostate and testis).

In hematopoietic cells, ATG2B is expressed in

CD34+ purified hematopoietic progenitors and

CD36+ erythroblasts or CD41+ megakaryocytes

derived from CD34+ progenitors cultured in vitro

(Saliba et al, 2016)

Localisation

ATG2B is mainly localized in the nucleus.

Function

Autophagy is an intracellular degradation system by

which cytoplasmic materials are enclosed by the

autophagosomes and transferred to lysosomes before

degradation. The autophagy process has been

extensively studied in yeast; 35 autophagy-related

genes (ATG) have been identified, of which 16 are

currently known in humans . This cellular process is

a highly conserved among species. In humans, two

ATG2 proteins, ATG2A and ATG2B, have

redundant functions and are required for

autophagosome formation (Velikkakath AK et al ,

2012).

Homology 44.5% of human ATG2B residues are identical to

those of human ATG2A.

Mutations

Germinal

A germline 14q32.2 head-to-tail duplication of 700

kb has been associated with familial myeloid

malignancies (Saliba et al , 2015). The germline

duplication includes the genes TCL1A, GSKIP,

ATG2B, BDKRB1, BDKRB2 and the first exon of

AK7. The overexpression of ATG2B and GSKIP

that are expressed in myeloid cells, enhances

hematopoietic progenitor differentiation,

particularly of megacaryocytes. The development of

myeloid malignancies required the cooperation of

both genes with the myeloproliferative neoplasms

(MPN) driver JAK2 Val617Phe mutation, MPL or

CALR mutations. The mechanism of cooperation

between ATG2B and GSKIP with MPN driver

mutations remains unknown.

The germline duplication with the same distal and

proximal breakpoints has only been identified in

MPN families originated from West Indies

(Martinique) suggesting a founder effect.

Somatic

A loss-of-function somatic mutation (c.3120delA,

p.Lys1040fs) in gastric carcinomas (15.6%) and in

colorectal carcinomas (11.6%) (Klionsky DJ, 2009).

Implicated in

Familial myeloproliferative neoplasms (MPN)

Disease

Familial MPN, in particular, essential

thrombocythemia progressing to myelofibrosis

and/or acute myeloid leukemia and primary

myelofibrosis, with autosomal dominant inheritance

and originated from West-indies (Martinique) may


The predisposition is highly penetrant (80%) and is

characterized by an earlier age of MPN onset in

comparison to sporadic cases (41 years versus > 60

years). The spectrum of acquired driver mutations

(JAK2 Val617Phe, MPL and CALR mutations) is

similar to the spectrum of mutations in sporadic

MPN cases.

Prognosis

The percentage of transformation is close to 50% in

these familial MPN cases and is related to the

detection of mutations affecting epigenetic regulator

genes such as TET2 IDH1 or IDH2.


Disease

AML originated from West-indies (Martinique) may


Prognosis

The prognosis of the disease is also linked to the

detection of acquired mutations in TET2, IDH1 or in

IDH2.

No TP53 mutation was found, contrary to what was

observed in AML evolving from MPN, suggesting a

different pathway for leukemic transformation.

Gastric carcinoma

Loss-of-functions somatic mutations in ATG genes

(ATG2B, ATG5, ATG9B and ATG12) are identified

ATG2B (Autophagy-related 2B) Bellanné-Chantelot C, Plo I


in 28% of gastric carcinomas with high

microsatellite instability. These mutations may

contribute to cancer development by deregulating

the autophagy process (Kang et al, 2009).

Colorectal cancer

Loss-of-functions somatic mutations in ATG genes

(ATG2B, ATG5, ATG9B and ATG12) are identified

in 28% of colorectal carcinomas with high

microsatellite instability. These mutations may

contribute to cancer development by deregulating

the autophagy process (Kang et al, 2009).

References Kang MR, Kim MS, Oh JE, Kim YR, Song SY, Kim SS, Ahn CH, Yoo NJ, Lee SH. Frameshift mutations of autophagy-related genes ATG2B, ATG5, ATG9B and ATG12 in gastric and colorectal cancers with microsatellite

instability. J Pathol. 2009 Apr;217(5):702-6

Klionsky DJ. Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol. 2007 Nov;8(11):931-7

Saliba J, Saint-Martin C, Di Stefano A, Lenglet G, Marty C, Keren B, Pasquier F, Valle VD, Secardin L, Leroy G, Mahfoudhi E, Grosjean S, Droin N, Diop M, Dessen P, Charrier S, Palazzo A, Merlevede J, Meniane JC, Delaunay-Darivon C, Fuseau P, Isnard F, Casadevall N, Solary E, Debili N, Bernard OA, Raslova H, Najman A, Vainchenker W, Bellanné-Chantelot C, Plo I. Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies. Nat Genet. 2015 Oct;47(10):1131-40

Velikkakath AK, Nishimura T, Oita E, Ishihara N, Mizushima N. Mammalian Atg2 proteins are essential for autophagosome formation and important for regulation of size and distribution of lipid droplets. Mol Biol Cell. 2012 Mar;23(5):896-909


Bellanné-Chantelot C, Plo I. ATG2B (Autophagy-related 2B). Atlas Genet Cytogenet Oncol Haematol. 2017; 21(6):205-207.

Leukaemia Section Short Communication




Primary mediastinal B-cell lymphoma (PMBL) Luis Miguel Juárez Salcedo, Samir Dalia

Principe de Asturias University Hospital, Madrid, Spain (LMJS); Oncology and Hematology, Mercy

Clinic Joplin, Joplin, MO, USA (SD); [email protected].

Published in Atlas Database: September 2016

Online updated version : http://AtlasGeneticsOncology.org/Anomalies/PrimMediastiBLymphomID1477.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68253/09-2016-PrimMediastiBLymphomID1477.pdf DOI: 10.4267/2042/68253


Abstract Review on primary mediastinal B-cell lymphoma,

with data on clinics, and the genes involved.

Keywords

primary mediastinal B-cell lymphoma; diffuse large

B-cell lymphoma

Identity

Other names

Thymic large B-cell lymphoma

Primary mediastinal (thymic) large B-cell

lymphoma

Mediastinal Large B-cell lymphoma

Clinics and pathology

Disease

PMBL is a subtype of diffuse large B-cell lymphoma

(DLBCL) that arises in the thymus. It accounts for 2-

4% on non-Hodgkin lymphoma and 10% of DLBCL.

It is epidemiology, clinically and biologically

distinct from the other subtypes of DLBCL. Similar

to nodular sclerosis Hodgkin lymphoma (NSHL)

arising in the mediastinum, it is likely derived from

thymic B cells (Dunleavy et al., 2015)

Phenotype/cell stem origin An origin from medullary thymic B cells has been

proposed for this disease.

PMBL has a B-cell phenotype and express CD20 and

pan B-cell markers such as CD79a, CD 45, CD 19

and CD22, but tumor cells do not express

surface immunoglobulin, therefore, monoclonality

cannot be established by Κ and λ staining. B-cell

transcription factors including PAX-5, OCT2 and

BOB1 are typically strongly expressed. CD23

expression is present in almost 66% of cases; CD30

is expressed in 78% whereas CD 15 is usually

negative, although one third of patients are positive.

High expression of BCL2 and PD1 has been

described (Bledsoe et al., 2016).

CD21 and class I and/or II histocompatibility

molecules have been claimed to be absent. Bcl-2

protein seems to be generally expressed, while

fragmentary data are available concerning the

occurrence of some molecules, such as CD10,

MUM1/IRF4, PAX5/BSAP (B-cell Specific

Activating Protein), Bcl-6.

Epidemiology

Typically presents in adolescents and young adults

with a median age of 35 years and a female

predominance with a male.female ratio of 1:2.

(Gaulard et al., 2008).

Clinics

PMBL is an aggressive disease manifested by a

localized, bulky mediastinal mass, often with pleural

and pericardial effusions.

Symptoms at diagnosis are caused by the mediastinal

mass, and complications such as superior vena cava

syndrome are common at presentation.

Regional lymph nodes may be involved, but spread

to distant nodal sites is uncommon. Less frequent,

the disease involves extranodal sites, including the

lung, kidneys, gastrointestinal organs or brain.

Pathology

Morphologically, the thymic B-cells are medium to

large cells having round or lobulated nuclei and

abundant cytoplasm. In most cases,

Primary mediastinal B-cell lymphoma (PMBL) Juárez Salcedo LM, Dalia S


compartmentalizing sclerosis is observed, and

sometimes tumor cells can resemble Hodgkin/Reed

Sternberg cells.

The nodal architecture is typically diffuse, with

occasional cases showing focal nodularity, and

necrosis is sometimes seen.

Treatment

In making decisions about the initial treatment one

must consider the long-term complications of

mediastinal radiation in this population of patients

who are predominantly young women.

R-CHOP followed by radiation has been effective in

low-risk patients.

In high-risk disease and high rate of primary

refractory disease DA- EPOCH-R without radiation

is the best treatment option, followed or not of

autologous stem cell transplantation.

Prognosis

Although the international prognosis index (IPI) is

useful in DLBCL, its use in PMBL could be limited

by the young age distribution and its typical

mediastinal presentation.

Lactate dehydrogenase level, male sex, performance

status and advanced-stage disease may be useful

predictors of survival.

Genetics

Note

Among the most common genetic alterations in

PMBL are abnormalities on chromosome 9p and 2p.

The 9p region encodes JAK2, which then activates

the STAT6 through phosphorylation. This STAT 6

phosphorylated can transcriptionally repress BCL6.

Also in 9p region, CD274 and PDCD1LG2

(programmed death ligands (PDLs) 1 and 2

respectively) are rearranged at a frequency of 20%.

Gains or amplifications of REL may be seen at 2p.

One third of cases may have gains in chromosome

X.

New two recurrent mutations have been identified;

one of these is the recurrent somatic coding-

sequence mutation in the PTPN1 gene (also found in

Hodgkin lymphoma cases) and the recurrent point

mutation in the XPO1 (exportin 1 gene or CRM1),

which results in the Glu571Lys missense

substitution, in refractory/relapsed PMBL (Jardin et

al., 2016).

The XPO1 mediate the translocation of numerous

RNAs and cellular regulatory proteins, including

tumor suppressor proteins (TP53, BRCA1, NPM1,

APC and FOXO).

References Bishop PC, Wilson WH, Pearson D, Janik J, Jaffe ES, Elwood PC. CNS involvement in primary mediastinal large B-cell lymphoma. J Clin Oncol. 1999 Aug;17(8):2479-85

Bledsoe JR, Redd RA, Hasserjian RP, Soumerai JD, Nishino HT, Boyer DF, Ferry JA, Zukerberg LR, Harris NL, Abramson JS, Sohani AR. The immunophenotypic spectrum of primary mediastinal large B-cell lymphoma reveals prognostic biomarkers associated with outcome. Am J Hematol. 2016 Oct;91(10):E436-41

Dunleavy K, Wilson WH. Primary mediastinal B-cell lymphoma and mediastinal gray zone lymphoma: do they require a unique therapeutic approach? Blood. 2015 Jan 1;125(1):33-9

Gaulard P, Harris NL, Pileri SA, et al. Primarymediastinal (thymic) large B-cell lymphoma.. WHO Classification of Tumours of Hae-matopoietic and Lymphoid Tissues In:Swerdlow SH, Campo E, Harris NL, Jaffe ES,Pileri SA, Stein H, Thiele J, Vardiman JW, editors. Lyon: IARCPress; 2008. pp 250-251.2.

Jardin F, Pujals A, Pelletier L, Bohers E, Camus V, Mareschal S, Dubois S, Sola B, Ochmann M, Lemonnier F, Viailly PJ, Bertrand P, Maingonnat C, Traverse-Glehen A, Gaulard P, Damotte D, Delarue R, Haioun C, Argueta C, Landesman Y, Salles G, Jais JP, Figeac M, Copie-Bergman C, Molina TJ, Picquenot JM, Cornic M, Fest T, Milpied N, Lemasle E, Stamatoullas A, Moeller P, Dyer MJ, Sundstrom C, Bastard C, Tilly H, Leroy K. Recurrent mutations of the exportin 1 gene (XPO1) and their impact on selective inhibitor of nuclear export compounds sensitivity in primary mediastinal B-cell lymphoma Am J Hematol 2016 Sep;91(9):923-30


Juárez Salcedo LM, Dalia S. Primary mediastinal B-cell lymphoma (PMBL). Atlas Genet Cytogenet Oncol Haematol. 2017; 21(6):208-209.

Leukaemia Section Review




t(2;11)(p21;q23) without KMT2A (MLL) rearrangement Ana L. Ruano, Shashirekha Shetty

Robert J. Tomisch Pathology, Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio

(ALR, SS), and University Hospitals, Case Western Reserve University, Cleveland, Ohio (SS),

USA; [email protected] and [email protected]

Published in Atlas Database: August 2016

Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0211p21q23ID1333.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68254/08-2016-t0211p21q23ID1333.pdf DOI: 10.4267/2042/68254


Abstract Forty five cases carrying the t(2;11)(p21;q23) have

been reported in the literature, mostly in

myelodysplastic syndromes (MDS) and acute

myeloid leukemia (AML). Some of these cases

involve rearrangements of the the MLL gene (also

known as KMT2A), on 11q23, which confers a more

aggressive behavior in myeloid neoplasms. Several

individual case reports, as well as series such as 19

cases reported by Bousquet et al., 2008 and 7 cases

by Dvorak et al., 2014, describe myeloid neoplasms

carrying the t(2;11)(p21;q23)

without an MLL gene rearrangement, with possible

prognostic implications. The authors of this paper

describe two additional cases from their institution.

Keywords

Myelodysplastic syndrome, acute myeloid leukemia,

t(2;11).

Identity

Other names

Acute myeloid leukemia and myelodysplastic

syndrome with t(2;11)(p21;q23) without MLL gene

rearrangement.

Representative images of karyotype showing rearrangement between chromosomes 2 and 11, and FISH images showing lack of MLL gene rearrangement.

t(2;11)(p21;q23) without KMT2A (MLL) rearrangement Ruano AL, Shetty S



Disease

Phenotype/cell stem origin

Myeloid blasts.

Thirty two case are available: 2 chronic

myeloproliferative cases, 18 myelodysplastic

syndromes (MDS), and 12 cases of acute myeloid

leukemia (AML). Diagnoses were: chronic

myelogenous leukemia harbouring the

t(9;22)(q34;q11) (CML, 1 case), polycythemia vera

(PV, 1 case), myelodysplastic/myeloproliferative

overlap syndrome (MDS/MPN, 1 case), refractory

anemia (RA, 1 case), refractory anemia with excess

blasts (RAEB, RAEB-I, RAEB-II, 5 cases),

refractory cytopenia with multilineage dysplasia

(RCMD, 2 cases), RCMD with ring sideroblasts

(RCMD-RS, 1 case), unclassifiable MDS (MDS-U,

1 case), low grade MDS NOS (7 cases); AML NOS

(3 cases), AML-M0 (1 case), AML-M1 (1 case),

AML-M2 (3 cases), AML-M4 (2 cases) and AML-

M5 (2 cases). Ten of the twelve AML cases were

classified either as having multilineage dysplasia or

as arising from MDS (chronic myelomonocytic

leukemia , refractory anemia). In two cases,

dysplasia could not be assessed (Harrison et al.,

1998; Gozzetti et al., 2003; Royer-Pekora et al.,

2003; Bousquet et al., 2008; Dvorak et al., 2014;

McCormick et al., 2014; Ruano and Shetty,

unpublished observation)

The authors of this paper describe two additional

cases, above included (Ruano and Shetty,

unpublished observation): one in a patient diagnosed

with myelodysplastic/myeloproliferative

(MDS/MPN) overlap syndrome best classified as

atypical chronic myeloid leukemia (CML),

BCR/ABL negative; another patient presented with

acute monoblastic leukemia, later classified as AML

with myelodysplasia-related changes after obtaining

knowledge on the cytogenetic findings.

Epidemiology

Two cases consisted of a 44 year old female and a 54

year old male (Ruano and Shetty, unpublished

observation).

Altogether, there were 26 male and 6 female

patients. Median age at diagnosis was 56-57 years

(range 37-74).

Clinics

The authors describe a case of a 54 year old male that

initially presented with ankle swelling and left upper

quadrant discomfort noted to have marked

leukocytosis (WBC=237,000/µL) and macrocytic

anemia (Hb=10.1 g/dL ; MCV=101.9 fl) associated

with massive splenomegaly.

This patient was diagnosed with atypical CML,

BCR/ABL negative. The second patient is a 44 year

old female with no significant medical history that

presented with upper and lower extremity pain and

found to be pancytopenic with 2% circulating blasts.

She was eventually diagnosed with acute myeloid

leukemia with myelodysplasia-related changes.

Pathology

Five of the seven cases reported by Dvorak et al.,

2014 showed marked megakaryocytic dysplasia.

The case described by McCormick et al., 2014

showed a hypercellular bone marrow (95%) with

increased megakaryoctyes ranging from small

hypolobated forms to large and normally lobated.

Bone marrow aspirate showing intermediate size blasts with fine nuclear chromatin and moderate basophilic cytoplasm with occasional small azurophiic granules and vacuoles. The blasts were diffusely positive for alpha-naphthyl butyrate esterase and

negative for myeloperoxidase cytochemistries (insert).



Hypercellular bone marrow (>95%) showing sheets of immature mononuclear cells with fine chromatin and prominent nucleoli, consistent with blasts.

From the cases reported by the authors of this paper,

the bone marrow aspirate and biopsy from the 54

year old patient with atypical CML, BCR/ABL

negative showed granulocytic hyperplasia with left

shift with occasional dyserythropoiesis and

dysgranulopoiesis. There was more prominent

dysmegakaryopoiesis consisting of small,

hypolobated forms with occasional

micromegakaryocytes. Blasts represented 3% of

bone marrow elements. One year later, the patient

presented with acute myeloid leukemia with 40%

circulating blasts expressing CD5, CD7, CD13,

CD33, CD34, CD117, and HLA-DR, with dim

expression of CD56. Two follow-up bone marrows

showed persistent involvement by AML.

The bone marrow aspirate and biopsy from the 44

year old female with AML showed 89% blasts

expressing CD13 (dim), CD33, CD38, CD45 (dim),

CD56, CD64, CD65 (bright), HLA-DR, and CD117

(on a subset). performed on the bone marrow aspirate

shows 69% blasts which are positive for CD4, CD13

(dim), CD33, CD38, CD45 (dim), CD56, CD64,

CD65 (bright), HLA-DR, and CD117 (subset).

Cytochemical stains showed that the blasts were

negative for myeloperoxidase and positive for alpha-

naphthyl butyrate esterase. See Figure 2 and 3.

Treatment The patient reported by Gozzeti et al., 2003 was

treated with cytarabine for 7 days, achieving a partial

remission. His disease progressed afterwards for

what he was treated with various

chemotherapeutic regimens but died 1 year after

diagnosis. The patient reported by Royer-Pokora et

al., 2003 was treated with imatinib achieving

complete response that lasted for 22 months, when

the case report was written.

The seven patients reported by Dvorak et al., 2014

were treated either with symptomatic or

cytoreductive therapy. One patient with deletion 5q

was treated with lenalidomide but had only a partial

response to treatment. Two patients underwent

peripheral stem cell transplantation, after which one

had stable disease but the other transformed to AML.

The median overall survival for this small cohort was

72 months and at the time of publication, 2 patients

were alive and 5 had died.

The patient reported by McCormick et al., 2014

remained clinically stable 70 months after initial

diagnosis, requiring only periodic phlebotomies.

The 54 year old patient described by this page's

authors was initially treated with hydroxyurea after

being diagnosed with atypical CML. He transformed

to AML 14 months later and was treated with 7+3,

ara-C and idarubicin. Due to persistent disease he

was started on a new cycle of chemotherapy which

was complicated by fever and altered mental status

eventually leading to patient's death approximately 1

month later. The 44 year old patient diagnosed with

AML with myelodysplasia related changes was

treated with 7+3 regimen, with cytarabine and

daunorubicin and had 2 negative bone marrows at 14

days and 1 month after treatment was started.

She remained clinically stable but was lost to follow-

up 1 year after diagnosis.



Prognosis

Dvorak et al., 2014 determined that the median

survival of MDS patients harbouring the

t(2;11)(p21;q23) was significantly greater than that

of MDS patients with complex karyotype or trisomy

8 as sole abnormality (72 vs 7.5 and 57 months,

respectively, p=0.0007). Other studies have placed

the t(2;11)(p21;q23) in the intermediate risk

category. However, the MLL gene status was not

evaluated. Studies in larger groups of patients, also

possibly including patients with AML, are needed in

order to determine if the t(2;11)(p21;q23) without

MLL rearrangement truly conveys a better

prognosis.

Cytogenetics

Cytogenetics morphological

The case described by Harrison et al., 1998 showed

a 46XX, t(2;11)(p21;q23), del(5q)(q13q33)

[24]/46XX[1] karyotype and was negative for MLL

gene rearrangements by Southern Blot. The case

described by Gozzetti et al., 2003 had a 46XX,

t(2;11)(p21;q23)[14] karyotype and was negative for

an MLL rearrangement by FISH. The CML case

reported by Royer-Pekora et al., 2003 initially had

both, a t(9;22)(q34;q11) and a t(2;11)(p21;q23) on

all analysed cells. After the patient achieved major

molecular and cytogenetic response to imatinib, a

new clone containing only the t(2;11) emerged. This

translocation was not present on skin fibroblasts

from which the authors conclude that it was not

present constitutionally.

Among the 19 cases reported by Bousquet et al.,

2008, the t(2;11)(p21;q23) was the sole cytogenetic

abnormality in 5 cases, and was associated with

other abnormalities in the other 14 cases including

deletion 5q (8 cases) and chromosome 7

abnormalities (4 cases). All cases were negative for

MLL gene rearrangements by FISH, and an

alternative breakpoint located downstream from

MLL was identified by PCR-based molecular

techniques, without a definitively identified gene.

They also describe overexpression of microRNA

(MiR) -125b in their patient series.

All seven cases reported by Dvorak et al., 2014

showed the t(2;11)(p21;q23). In 2 cases, this was the

only cytogenetic abnormality, in 4 cases a deletion

of 5q was also present in the main clone, and in 1

patient the deletion 5q was present in a subclone.

They were all negative for MLL gene

rearrangements by FISH.

Cytogenetic analysis from the case described by

McCormick et al., 2014 showed four lines: one

showing a 46XY normal male karyotype, two

showing the t(2;11)(p21;q23-24), one of which also

showed del(5)(q15q31), and a fourth one showing

only the del5q. There was no MLL gene

rearrangement detected by FISH and allele specific

polymerase chain reaction (PCR) was negative for a

JAK2V617F mutation. However, a mutation in

JAK2 exon 12 was identified.

From the cases described by the authors of this page,

the karyotype of the 54 year old male with atypical

CML was reported as 46,XY,t(2;11)(p21;q23). The

karyotype of the 44 year old female with AML was

reported as

47,XX,t(2;11)(p21;q23),+8[16]/47,idem,+i(8)(q10)[

4]. Both cases were negative for MLL gene

rearrangement by FISH (see Figure 1).

Genes involved and proteins

Note

The gene on 11q23 involved in these translocations

has not been yet identified. Bousquet et al., 2008

determined through FISH that the breakpoint in their

cases appeared to be located downstream from the

MLL region. By PCR, they assessed expression of

several genes/sequence tags known to be located in

this region but did not find altered expression of any

of them. They did find, however, that their series of

patients showed overexpression of miR -125b (6- to

90-fold) when compared to other patients with MDS

or AML without the translocation. McCormick et al.,

2014 also found a 200-fold overexpression of miR-

125b in their case.

miR-125b originates from chromosomes 11q24

(MIR125B1 ) and 21q21 (MIR125B2 ) It is a

regulator of normal hematopoiesis and exerts its

oncogenic effect through several mechanisms

including arrest of myeloid/monocytic

differentiation, promoting stem cell renewal and

targeting intermediaries in the TP53 pathway.

Besides AML/MDS with t(2;11)(p21;q23), miR-

125b has also found to play a role in pediatric

acutepromyelocytic leukemia , acute

megakaryoblastic leukemia of trisomy 21, and

precursor B-cell acute lymphoblastic leukemia (B-

ALL) (McCormick et al., 2014).

References Bousquet M, Quelen C, Rosati R, Mansat-De Mas V, La Starza R, Bastard C, Lippert E, Talmant P, Lafage-Pochitaloff M, Leroux D, Gervais C, Viguié F, Lai JL, Terre C, Beverlo B, Sambani C, Hagemeijer A, Marynen P, Delsol G, Dastugue N, Mecucci C, Brousset P. Myeloid cell differentiation arrest by miR-125b-1 in myelodysplastic syndrome and acute myeloid leukemia with the t(2;11)(p21;q23) translocation. J Exp Med. 2008 Oct 27;205(11):2499-506

Dvorak P, Lysak D, Vokurka S, Michalova K, Sarova I, Jonasova A, Hruba M, Rykovska A, Subrt I. The translocation t(2;11)(p21;q23) without MLL gene rearrangement--a possible marker of good prognosis in myelodysplastic syndrome patients. Hematol Oncol. 2014 Jun;32(2):82-6



Fleischman EW, Reshmi S, Frenkel MA, Konovalova WI, Guleva GP, Kulagina OE, Konstantinova LN, Tupitsyn NN, Rowley JD. MLL is involved in a t(2;11)(p21;q23) in a patient with acute myeloblastic leukemia. Genes Chromosomes Cancer. 1999 Feb;24(2):151-5

Gozzetti A, Tozzuoli D, Crupi R, Raspadori D, Fabbri A, Lauria F. A case of acute myelogenous leukemia: myelodysplastic syndrome with t(2;11)(p21;q23) without MLL rearrangement. Cancer Genet Cytogenet. 2003 Jul 15;144(2):177-8

Harrison CJ, Cuneo A, Clark R, Johansson B, Lafage-Pochitaloff M, Mugneret F, Moorman AV, Secker-Walker LM. Ten novel 11q23 chromosomal partner sites. European 11q23 Workshop participants. Leukemia. 1998 May;12(5):811-22

McCormick SR, Higgins RR, Grutkoski PS, Bousquet M, Quelen C, Bartholomaus LM, Brousset P. Myeloid

neoplasm with translocation t(2;11)(p21;q23-24), elevated microRNA 125b-1, and JAK2 exon 12 mutation. Br J Haematol. 2015 Apr;169(2):290-3

Royer-Pokora B, Hildebrandt B, Redmann A, Herold C, Kronenwett R, Haas R, Drechsler M, Wieland C. Simultaneous occurrence of a t(9;22) (Ph) with a t(2;11) in a patient with CML and emergence of a new clone with the t(2;11) alone after imatinib mesylate treatment. Leukemia. 2003 Apr;17(4):807-10


Ruano AL, Shetty S. t(2;11)(p21;q23) without KMT2A (MLL) rearrangement. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(6):210-214.





t(1;12)(p36;p13) ETV6/PRDM16 Francois P. Duhoux, Hélène A. Poirel

Cliniques universitaires Saint-Luc, Université catholique de Louvain / helene.antoine-

[email protected]


Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0112p36p13ID1697.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68255/08-2016-t0112p36p13ID1697.pdf DOI: 10.4267/2042/68255


Abstract Review on t(1;12)(p36;p13) translocations, with data

on clinics, and the genes involved.

Keywords

chromosome 1; chromosome 12; t(1;12)(p36;p13);

PRDM16; ETV6


Disease

Acute myeloid leukaemia (AML).


AML M4 according to immunophenotyping vs M1

according to cytology.

Epidemiology

Found in one case of AML in a 46 years old female

Duhoux et al., 2012).

Cytology

Leukemic infiltrate of myeloid origin (blasts I and

II); high proportion of myeloid blast cells and

restricted percentage of monocytes.

Prognosis

The patient died 12 months after diagnosis.

Cytogenetics


The t(1;12)(p36;p13.2) was the sole anomaly.


PRDM16 (PR domain containing 16)

Location

1p36.32

DNA/RNA

11 splice variants

Protein

1276 amino acids and smaller proteins. Contains a

N-term PR domain; 7 Zinc fingers, a proline-rich

domain, and 3 Zinc fingers in the C-term. Binds

DNA. Transcription activator; PRDM16 has an

intrinsic histone methyltransferase activity.

PRDM16 forms a transcriptional complex with

CEBPB. PRDM16 plays a downstream regulatory

role in mediating TGFB signaling (Bjork et al.,

2010). PRDM16 induces brown fat determination

and differentiation. PRDM16 is expressed

selectively in the earliest stem and progenitor

hematopoietic cells, and is required for the

maintenance of the hematopoietic stem cell pool

during development.

t(1;12)(p36;p13) ETV6/PRDM16 Duhoux FP, Poirel HA


Left: FISH using the LSI® ETV6 probe : the probe is split between the der(1) and the der(12. Right: FISH using specific probes for PRDM16 (RP5-907A6 and RP1-163G9): the RP1-163G9 probe is split between the der(1) and the der(12), the RP5-907A6

probe is translocated to the der(12)PROBES RP5-907A6 (FITC), RP1-163G9 (Cy3) and LSI® ETV6

PRDM16 is also required for survival, cell-cycle

regulation and self-renewal in neural stem cells

(Chuikov et al., 2010; Kajimura et al., 2010; Aguilo

et al., 2011; Chi and Cohen, 2016).

ETV6 (ets variant 6)

Location

12p13.2

Protein

452 amino acids. The ETV6 protein contains from

N-term to C-Term a HLH (helix-loop-helix, aa 40-

124) domain (also referred to as the pointed or sterile

alpha motif domain), responsible for hetero- and

homodimerization, an internal domain, involved in

the recruitment of a repression complex

including NCOR1 (17p12), NCOR2 (12q24.31),

SIN3A (15q24.2), and SIN3B (19p13.11), and an

ETS domain (aa 339-420), responsible for sequence

specific DNA-binding and protein-protein

interaction (De Braekeleer et al., 2014).

Result of the chromosomal anomaly

Hybrid gene

Description

ETV6 exon 4 is fused to PRDM16 exon 2.

Detection

PCR, FISH.

Schematic representation of the putative ETV6-PRDM16 fusion protein, PRD = prolin-rich domain, DBD1 = DNA-binding domain 1, PRR = prolin-rich domain, RD = repressor domain, DBD2 = DNA-binding domain 2, AD = acidic domain.

t(1;12)(p36;p13) ETV6/PRDM16 Duhoux FP, Poirel HA


References Aguilo F, Avagyan S, Labar A, Sevilla A, Lee DF, Kumar P, Lemischka IR, Zhou BY, Snoeck HW. Prdm16 is a physiologic regulator of hematopoietic stem cells. Blood. 2011 May 12;117(19):5057-66

Bjork BC, Turbe-Doan A, Prysak M, Herron BJ, Beier DR. Prdm16 is required for normal palatogenesis in mice. Hum Mol Genet. 2010 Mar 1;19(5):774-89

Chi J, Cohen P. The Multifaceted Roles of PRDM16: Adipose Biology and Beyond. Trends Endocrinol Metab. 2016 Jan;27(1):11-23

Chuikov S, Levi BP, Smith ML, Morrison SJ. Prdm16 promotes stem cell maintenance in multiple tissues, partly by regulating oxidative stress. Nat Cell Biol. 2010 Oct;12(10):999-1006

De Braekeleer E, Douet-Guilbert N, De Braekeleer M.. ETV6 (ets variant 6). Atlas Genet Cytogenet Oncol Haematol. 2014; 18(12):886-899.

Duhoux FP, Ameye G, Montano-Almendras CP, Bahloula

K, Mozziconacci MJ, Laibe S, Wlodarska I, Michaux L, Talmant P, Richebourg S, Lippert E, Speleman F, Herens C, Struski S, Raynaud S, Auger N, Nadal N, Rack K, Mugneret F, Tigaud I, Lafage M, Taviaux S, Roche-Lestienne C, Latinne D, Libouton JM, Demoulin JB, Poirel HA; Groupe Francophone de Cytogénétique Hématologique (GFCH); Belgian Cytogenetic Group for Haematology and Oncology (BCG-HO).. PRDM16 (1p36) translocations define a distinct entity of myeloid

malignancies with poor prognosis but may also occur in lymphoid malignancies. Br J Haematol. 2012 Jan;156(1):76-88. doi: 10.1111/j.1365-2141.2011.08918.x. Epub 2011 Nov 3.

Kajimura S, Seale P, Kubota K, Lunsford E, Frangioni JV, Gygi SP, Spiegelman BM.. Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-beta transcriptional complex. Nature. 2009 Aug 27;460(7259):1154-8. Epub 2009 Jul 29.


Duhoux FP, Poirel HA. t(1;12)(p36;p13) ETV6/PRDM16. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(6):215-217.





t(1;1)(p36;p36) PRDM16/SKI Jean-Loup Huret

Medical Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021

Poitiers, France. [email protected]





Abstract Review on t(1;1)(p36;p36) PRDM16/SKI

translocations, with data on clinics, and the genes

involved.

Keywords

chromosome 1; t(1;1)(p36;p36), SKI; PRDM16


Disease



Only one case to date (Masetti et al 2014).

Clinics

An 8-year-old child was diagnosed with acute

monoblastic leukemia with differentiation (AML-

M5b).

Prognosis

5 years after the allograft, the patient was alive and

disease-free.

Cytogenetics

Additional anomalies

The patient also had a t(7;21)(p22;q22) RUNX1 /

USP42, and a del(5)(q14q34)



Location

1p36.32

DNA/RNA

11 splice variants

Protein



domain, and 3 Zinc fingers in the C-term.

Binds DNA.

Transcription activator; PRDM16 has an intrinsic

histone methyltransferase activity. PRDM16 forms a

transcriptional complex with CEBPB.

PRDM16 plays a downstream regulatory role in

mediating TGFB signaling (Bjork et al., 2010).

PRDM16 induces brown fat determination and

differentiation.

PRDM16 is expressed selectively in the earliest stem

and progenitor hematopoietic cells, and is required

for the maintenance of the hematopoietic stem cell

pool during development. PRDM16 is also required

for survival, cell-cycle regulation and self-renewal in

neural stem cells (Chuikov et al., 2010; Kajimura et

al., 2010; Aguilo et al., 2011; Chi and Cohen, 2016).

SKI (SKI proto-oncogene)

Location

t(1;1)(p36;p36) PRDM16/SKI Huret JL


1p36.33

Protein

Negative regulator of the TGFB)/Smad signaling.

SKI and SKIL (SnoN) are transcriptional co-

repressors which interact with Smads, and repress

transcription induced by TGFB.

TGFB signaling suppresses tumor cell proliferation

at early stages of tumorigenesis but promotes

epithelial-to-mesenchymal transition (EMT), tumor

invasion, and metastasis at late malignant stages.

SKI interacts with the Hippo pathway.

SKI inhibites the transcription activity of TAZ as

well as its ability to promote transformation and

EMT (Rashidian et al., 2015).

High expression of SKI results in activation of

hematopoietic stem cells transcriptional programs

and an HSC autonomous repopulating advantage

that favors myeloid development through hepatocyte

growth factor (HGF) signaling and independently of

its ability to inhibit TGFB signaling. SKI is highly

expressed in chronic myeloid leukemia (CML) and

acute myeloid leukemia (AML) (Singbrant et al.,

2014). SKI has a critical role in the development of

neuronal and muscle cells or tissues. SKI mutations

have been identified in Shprintzen-Goldberg

syndrome (SGS) (Schepers et al., 2015).


Hybrid gene

Description

5' PRDM16 ? 3' SKI; breakpoint: AAG CTA GCC

AAA A - GT CTC CTC TGA

Fusion protein

Description

Fusion of PRDM16 exon 1 (MRSKARARKLAK) to

SKI exon 2 (VSSEPPASIRPK.)

References

Masetti R, Togni M, Astolfi A, Pigazzi M, Indio V, Rivalta B, Manara E, Rutella S, Basso G, Pession A, Locatelli F. Whole transcriptome sequencing of a paediatric case of de novo acute myeloid leukaemia with del(5q) reveals RUNX1-USP42 and PRDM16-SKI fusion transcripts. Br J Haematol. 2014 Aug;166(3):449-52

Rashidian J, Le Scolan E, Ji X, Zhu Q, Mulvihill MM, Nomura D, Luo K. Ski regulates Hippo and TAZ signaling to suppress breast cancer progression. Sci Signal. 2015 Feb 10;8(363):ra14

Schepers D, Doyle AJ, Oswald G, Sparks E, Myers L, Willems PJ, Mansour S, Simpson MA, Frysira H, Maat-Kievit A, Van Minkelen R, Hoogeboom JM, Mortier GR, Titheradge H, Brueton L, Starr L, Stark Z, Ockeloen C, Lourenco CM, Blair E, Hobson E, Hurst J, Maystadt I, Destrée A, Girisha KM, Miller M, Dietz HC, Loeys B, Van Laer L. The SMAD-binding domain of SKI: a hotspot for de novo mutations causing Shprintzen-Goldberg syndrome. Eur J Hum Genet. 2015 Feb;23(2):224-8

Singbrant S, Wall M, Moody J, Karlsson G, Chalk AM, Liddicoat B, Russell MR, Walkley CR, Karlsson S. The SKI proto-oncogene enhances the in vivo repopulation of hematopoietic stem cells and causes myeloproliferative disease. Haematologica. 2014 Apr;99(4):647-55

Aguilo F, Avagyan S, Labar A, Sevilla A, Lee DF, Kumar P, Lemischka IR, Zhou BY, Snoeck HW. Prdm16 is a physiologic regulator of hematopoietic stem cells. Blood. 2011 May 12;117(19):5057-66




Kajimura S, Seale P, Kubota K, Lunsford E, Frangioni JV, Gygi SP, Spiegelman BM. Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-beta transcriptional complex. Nature. 2009 Aug 27;460(7259):1154-8


Huret JL. t(1;1)(p36;p36) PRDM16/SKI. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(6):218-219.





t(1;3)(p36;q21) PSMD2/PRDM16 ??? Jean-Loup Huret




Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0103ID1002.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68257/09-2016-t0103ID1002.pdf DOI: 10.4267/2042/68257

This article is an update of : Hess JL. t(1;3)(p36;q21). Atlas Genet Cytogenet Oncol Haematol 2002;6(3) Cornillet-Lefebvre P, Daliphard S, Struski S. t(1;3)(p36;q21). Atlas Genet Cytogenet Oncol Haematol 2001;5(1) Huret JL. t(1;3)(p36;q21). Atlas Genet Cytogenet Oncol Haematol 1997;1(1)


Identity

This entity probably does not exist: 1- PSMD2 sits in 3q27, while the breakpoint is in

3q21;

2- PSMD2, a protein of the proteasome is well

known by its alias, RPN1, while the true RPN1, a

protein involved in N-glycosylation, sitting in 3q21,

is better known by its full name: Ribophorin I.

The translocation is therefore likely to be

t(1;3)(p36;q21) RPN1/PRDM16

Clinics and pathology Disease

Myeloid lineage (MDS, AML, therapy related AML,

CML, MPD); features similar to those of the

3q21q26 syndrome including normal or elevated

platelet count at diagnosis, megakaryocytic

hyperplasia and dysplasia. Very rarely in lymphoid

lineage

t(1;3)(p36;q21) G-banding (left) - Courtesy Diane H. Norback, Eric B. Johnson, and Sara Morrison-Delap, UW Cytogenetic Services; R-banding (right) Courtesy Pascale Cornillet-Lefebvre and Stéphanie Struski (above) and Christiane Charrin (below)

http://www.waisman.wisc.edu/cytogenetics/index.htmlx

http://www.waisman.wisc.edu/cytogenetics/index.htmlx

t(1;3)(p36;q21) PSMD2/PRDM16 ??? Huret JL



of 39 cases, there were: 22 myelodysplastic

syndromes (MDS) (17/22 transformed into

refractory acute myeloid leukemia (AML) of -M1 or

-M4 type), 8 de novo AML, 3 therapy-related MDS,

2 polycythemia vera, 1 essential thrombocythemia, 1

chronic myelogenous leukemia (CML), 1 multiple

myeloma, 1 waldenstrom's macroglobulinemia

Epidemiology

patients are aged: 30-80 yrs

Clinics

Roughly 50% of patients present with MDS, another

10% with therapy associated MDS, 25% with de

novo AML, and the remainder with a range of other

myeloproliferative disorders. The majority of MDS

patients transform into AML with a short

preleukemic phase.

Blood data: frequent thrombocytosis or normal

platelet count

Cytology

frequently characterized by

dysmegakaryocytopoiesis

Pathology

The pathology is typical of MDS, often with a

prominent monocytic component. Trilineage

dysplasia. Acute leukemias that evolve usually show

the morphology of M4 AML.

Treatment

Patients are treated with conventional chemotherapy

for AML.

Prognosis

Very poor so far: from 16 cases, median survival was

6 mths in AML, 20 mths in MDS

Cytogenetics

Note

Other rearrangements showing similar clinical

features include inv(3)(q21q26), t(3;3)(q21;q26),

t(3;5)(q21;q31), t(3;8)(q21;q24), and

t(3;21)(q26;q22). The breakpoints in 3q21 cluster in

a 50 kb region centromeric to the breakpoint in

inv(3)(q21;q26) and the ribophorin gene (RPN1).

The breakpoints at 1p36 are clustered in a 90 kb

region at 1p36.3.

Additional anomalies

del (5q) in 5 of 20 cases (1/4)


Mechanisms of Oncogenesis : The available data

suggest that transcription of MEL1 (MDS1/EVI1 -

like gene) is activated as a result of translocation

bringing the gene just 3' to RPN1 gene at 3q21.

MEL1 is a 1257 amino acid protein that is

homologous (63% similar in amino acid sequence)

to EVI. The mechanism of activation of MEL1 is

similar to EVI1 that is activated by juxtaposition 3'

to RPN1 in the t(3;3)(q21;q26) and 5' to RPN1 in the

inv(3)(q2126). It appears that MEL1 is normally

expressed in uterus and kidney and not in normal

hematopoietic cells or in leukemias that lack the

t(1;3)(p36;q31 The MEL1 protein contains 2 DNA

binding domains (7 C2H2 zinc finger repeats at the

amino terminus and 3 zinc finger repeats at the

carboxyl terminus). The amino terminal domain of

MEL1 contains a PRD domain, a motif also found in

the same location in the MDS1/EV1 protein but not

in MDS1). This is of interest because this domain is

also found in RIZ, PRDI-BF1, and egl-43 and is

homologous to the SET (Suvar3-9, Enhancer of

zeste, Trithorax) domain that present in MLL.

Inclusion of this domain in EVI1 appears to convert

EVI1 from a transcriptional repressor to an activator.

Therefore MEL1 may be a transcriptional activator.

The target genes of MEL1 have not been identified.

References Bitter MA, Neilly ME, Le Beau MM, Pearson MG, Rowley JD. Rearrangements of chromosome 3 involving bands 3q21 and 3q26 are associated with normal or elevated platelet counts in acute nonlymphocytic leukemia. Blood. 1985 Dec;66(6):1362-70

Bloomfield CD, Garson OM, Volin L, Knuutila S, de la Chapelle A. t(1;3)(p36;q21) in acute nonlymphocytic leukemia: a new cytogenetic-clinicopathologic association. Blood. 1985 Dec;66(6):1409-13

Grigg AP, Gascoyne RD, Phillips GL, Horsman DE. Clinical, haematological and cytogenetic features in 24 patients with structural rearrangements of the Q arm of chromosome 3. Br J Haematol. 1993 Jan;83(1):158-65

Huang S, Shao G, Liu L. The PR domain of the Rb-binding zinc finger protein RIZ1 is a protein binding interface and is related to the SET domain functioning in chromatin-mediated gene expression. J Biol Chem. 1998 Jun 26;273(26):15933-9

Marsden KA, Pearse AM, Collins GG, Ford DS, Heard S, Kimber RI. Acute leukemia with t(1;3)(p36;q21), evolution to t(1;3)(p36;q21), t(14;17)(q32;q21), and loss of red cell A and Le(b) antigens. Cancer Genet Cytogenet. 1992 Nov;64(1):80-5

Mochizuki N, Shimizu S, Nagasawa T, Tanaka H, Taniwaki M, Yokota J, Morishita K. A novel gene, MEL1, mapped to 1p36.3 is highly homologous to the MDS1/EVI1 gene and is transcriptionally activated in t(1;3)(p36;q21)-positive leukemia cells. Blood. 2000 Nov 1;96(9):3209-14

t(1;3)(p36;q21) PSMD2/PRDM16 ??? Huret JL


Moir DJ, Jones PA, Pearson J, Duncan JR, Cook P, Buckle VJ. A new translocation, t(1;3) (p36;q21), in myelodysplastic disorders. Blood. 1984 Aug;64(2):553-5

Secker-Walker LM, Mehta A, Bain B. Abnormalities of 3q21 and 3q26 in myeloid malignancy: a United Kingdom Cancer Cytogenetic Group study. Br J Haematol. 1995 Oct;91(2):490-501

Shimizu S, Suzukawa K, Kodera T, Nagasawa T, Abe T,

Taniwaki M, Yagasaki F, Tanaka H, Fujisawa S, Johansson B, Ahlgren T, Yokota J, Morishita K. Identification of breakpoint cluster regions at 1p36.3 and 3q21 in

hematologic malignancies with t(1;3)(p36;q21). Genes Chromosomes Cancer. 2000 Mar;27(3):229-38

Welborn JL, Lewis JP, Jenks H, Walling P. Diagnostic and prognostic significance of t(1;3)(p36;q21) in the disorders of hematopoiesis. Cancer Genet Cytogenet. 1987 Oct;28(2):277-85


Huret JL. t(1;3)(p36;q21) PSMD2/PRDM16 ???. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(6):220-222.





t(1;7)(p36;p12) IKZF1/PRDM16 Jean-Loup Huret







Abstract Review on t(1;7)(p36;p12) translocations, with data

on clinics, and the genes involved.

Keywords

chromosome 1; chromosome7; t(1;7)(p36;p12);

PRDM16; IKZF1


Disease

A t(1;7)(p36;p12) was found in a case of

myelodysplastic syndrome (MDS) (Duhoux et al.,

2012).

Clinics

A 66-year-old male patient who died 49 months after

diagnosis.

Cytogenetics


A +8 was present.



Location

1p36.32

DNA/RNA

11 splice variants

Protein



domain, and 3 Zinc fingers in the C-term. Binds

DNA. Transcription activator; PRDM16 has an

intrinsic histone methyltransferase activity.

PRDM16 forms a transcriptional complex with

CEBPB. PRDM16 plays a downstream regulatory

role in mediating TGFB signaling (Bjork et al.,

2010). PRDM16 induces brown fat determination

and differentiation. PRDM16 is expressed

selectively in the earliest stem and progenitor

hematopoietic cells, and is required for the

maintenance of the hematopoietic stem cell pool

during development. PRDM16 is also required for

survival, cell-cycle regulation and self-renewal in

neural stem cells (Chuikov et al., 2010; Kajimura et

al., 2010; Aguilo et al., 2011; Chi and Cohen, 2016).

IKZF1 (Ikaros family zinc finger 1)

Location

7p12.2

DNA/RNA

Numerous splice variants

Protein

519 amino acids. Contains 6 Zn fingers (act as DNA-

binding domain, and dimerization domain).

Transcription regulator. IKZF1 is involved in

chromatin remodeling complexes, such as

nucleosome-remodeling and histone deacetylation

(NuRD), and can both enhance and repress gene

transcription. IKZF1 plays a key role in

hematopoietic stem cell maintenance, B- and T-

lymphopoiesis, erythropoiesis and the fetal-to-adult

hemoglobin switch.

ETV6 and IKZF1 are components of a network of

heptad transcription factors (ERG, FLI1, GATA2,

LMO2, LYL1, RUNX1, and TAL1 (SCL). This

heptad acts in combination to regulate genes in

t(1;7)(p36;p12) IKZF1/PRDM16 Huret JL


hematopoietic stem and progenitor cells) that

regulate the expression of a number of hematopoietic

genes and whose high expression in acute myeloid

leukemia is associated with poor prognosis

(Unnikrishnan et al., 2016). IKZF1 deletions are

associated with unfavorable prognosis in childhood

B-cell precursor acute lymphoblastic leukemia

(ALL) (Boer et al., 2016), and is associated with a

higher relapse risk and worse survival in adults with

common B-cell ALL (Yao et al., 2016). IKZF1

mutations were found in cases of common variable

immunodeficiency syndrome with progressive B

lymphopenia and an increased risk of acute

lymphoblastic leukemia (Kuehn et al., 2016).


Hybrid gene

Description

5' IKZF1 - 3' PRDM16

Transcript

IKZF1 exon 3 joined to PRDM16 exon 3.

References Boer JM, van der Veer A, Rizopoulos D, Fiocco M, Sonneveld E, de Groot-Kruseman HA, Kuiper RP, Hoogerbrugge P, Horstmann M, Zaliova M, Palmi C, Trka J, Fronkova E, Emerenciano M, do Socorro Pombo-de-Oliveira M, Mlynarski W, Szczepanski T, Nebral K, Attarbaschi A, Venn N, Sutton R, Schwab CJ, Enshaei A, Vora A, Stanulla M, Schrappe M, Cazzaniga G, Conter V, Zimmermann M, Moorman AV, Pieters R, den Boer ML. Prognostic value of rare IKZF1 deletion in childhood B-cell precursor acute lymphoblastic leukemia: an international collaborative study. Leukemia. 2016 Jan;30(1):32-8

Unnikrishnan A, Guan YF, Huang Y, Beck D, Thoms JA, Peirs S, Knezevic K, Ma S, de Walle IV, de Jong I, Ali Z, Zhong L, Raftery MJ, Taghon T, Larsson J, MacKenzie KL, Van Vlierberghe P, Wong JW, Pimanda JE. A quantitative proteomics approach identifies ETV6 and IKZF1 as new regulators of an ERG-driven transcriptional network.

Nucleic Acids Res. 2016 Dec 15;44(22):10644-10661

Aguilo F, Avagyan S, Labar A, Sevilla A, Lee DF, Kumar P, Lemischka IR, Zhou BY, Snoeck HW. Prdm16 is a physiologic regulator of hematopoietic stem cells. Blood. 2011 May 12;117(19):5057-66




Duhoux FP, Ameye G, Montano-Almendras CP, Bahloula K, Mozziconacci MJ, Laibe S, Wlodarska I, Michaux L, Talmant P, Richebourg S, Lippert E, Speleman F, Herens C, Struski S, Raynaud S, Auger N, Nadal N, Rack K, Mugneret F, Tigaud I, Lafage M, Taviaux S, Roche-Lestienne C, Latinne D, Libouton JM, Demoulin JB, Poirel HA. PRDM16 (1p36) translocations define a distinct entity of myeloid malignancies with poor prognosis but may also occur in lymphoid malignancies. Br J Haematol. 2012 Jan;156(1):76-88

Kajimura S, Seale P, Kubota K, Lunsford E, Frangioni JV, Gygi SP, Spiegelman BM. Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-beta transcriptional complex. Nature. 2009 Aug 27;460(7259):1154-8

Kuehn HS, Boisson B, Cunningham-Rundles C, Reichenbach J, Stray-Pedersen A, Gelfand EW, Maffucci P, Pierce KR, Abbott JK, Voelkerding KV, South ST, Augustine NH, Bush JS, Dolen WK, Wray BB, Itan Y, Cobat A, Sorte HS, Ganesan S, Prader S, Martins TB, Lawrence MG, Orange JS, Calvo KR, Niemela JE, Casanova JL, Fleisher TA, Hill HR, Kumánovics A, Conley ME, Rosenzweig SD. Loss of B Cells in Patients with Heterozygous Mutations in IKAROS. N Engl J Med. 2016 Mar 17;374(11):1032-1043

Yao QM, Liu KY, Gale RP, Jiang B, Liu YR, Jiang Q, Jiang H, Zhang XH, Zhang MJ, Chen SS, Huang XJ, Xu LP, Ruan GR. Prognostic impact of IKZF1 deletion in adults with common B-cell acute lymphoblastic leukemia. BMC Cancer. 2016 Apr 11;16:269


Huret JL. t(1;7)(p36;p12) IKZF1/PRDM16. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(6):223-224.

Case Report Section




A pediatric case of acute lymphoblastic leukemia with t(2;9)(q12;q34) (RANBP2/ABL1 fusion) Marc De Braekeleer, Nadia Guéganic, Alexandra Schifferli, Joëlle Tchinda

Cytogenetics Laboratory, Faculty of Medicine, University of Brest, France

[email protected] (MdeB, NG)) Department of Hematology/Oncology, University

Children's Hospital Basel, Switzerland (AS) University Children's Hospital Zurich, Switzerland

(JT).

Published in Atlas Database: December 2015

Online updated version : http://AtlasGeneticsOncology.org/Reports/t0209q12q34BraekeleerID100084.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68259/12-2015-t0209q12q34BraekeleerID100084.pdf DOI: 10.4267/2042/68259


Clinics

Age and sex 21 months old female patient.

Previous history

no preleukemia

no previous malignancy

no inborn condition of note

Organomegaly

No hepatomegaly , no splenomegaly , no enlarged

lymph nodes , no central nervous system

involvement (t)

Blood

WBC : 77.5 (N: 6-17.5)X 109/l

HB : 29 (N: 105-135)g/dl

Platelets : 69 (N: 150-450)X 109/l

Blasts : 76%

Bone marrow : Hypercellular marrow, with 93.7%

blasts (small to middle-sized cells with large nucleus

and minimal cytoplasm).%

Cyto-Pathology Classification

Phenotype

Pre-B acute lymphoblastic leukemia.

Immunophenotype

cTDT, cCD79a, cIgM, CD19 and CD20 positive.

Rearranged Ig Tcr not performed.

Diagnosis Pre-B acute lymphoblastic leukemia.

Survival

Date of diagnosis 01-2014

Treatment

Protocol AIEOP-BFM ALL 2009 high risk.

Complete remission : Treatment related death : no

Relapse : no

Status A

Last follow up 12-2015

Survival 23 +months

Karyotype Sample bone marrow.

Banding G banding.

Results

46,XX,t(2;9)(q12-14;q34),add(5)(p14)[5]/46,sl,-

7,+mar[2]/46,XX[3]

Other molecular cytogenetics technics

fluorescence in situ hybridization(FISH) analysis

using ETV6-RUNX1, 5'MLL-3'MLL, CEP4,

CEP10, CEP17, 5'IGH-3'IGH, 3'TCF3-5'TCF3,

BCR-ABL1.

A pediatric case of acute lymphoblastic leukemia with t(2;9)(q12;q34) (RANBP2/ABL1 fusion)

De Braekeleer M, et al.


FISH experiments with BAC clones located in bands

2q12.1 to 2q14.2.

Other molecular cytogenetics results

All negative, except for BCR-ABL1 with 3 ABL1

signals and 2 BCR signals.

A split signal on der(2) and der(9) was found with

RP11-622D1, RP11-347H10, RP11-259O12, RP11-

348G16 and RP11-953L12. These BAC clones

overlap the RANBP2 gene and allow refinement of

the breakpoint to a 25kb region covering the 5' end

and the first three exons of RANBP2.

Other Molecular Studies

Technics: MLPA.

Results: Negative.

GTG banding showing chromosomes 2 and 9 and the derivatives der(2) and der(9).

FISH with BACs RP11-953L12 (spectrum green, located in 2q12 and containing RANBP2) and RP11-83J21 (spectrum orange, located in 9q34 and containing the 3' part of ABL1) and CEP9 (in aqua) showing one fusion signal on der(2).

No fusion is detected on der(9) because RP11-83J21 does not cover the 5' part of ABL1.

Comments We present here a unique case of pediatric acute

lymphoblastic leukemia. This fusion gene was

identified in another case by RNA-sequencing

(Roberts et al., 2012).

A pediatric case of acute lymphoblastic leukemia with t(2;9)(q12;q34) (RANBP2/ABL1 fusion)

De Braekeleer M, et al.


References Roberts KG, Morin RD, Zhang J, Hirst M, Zhao Y, Su X, Chen SC, Payne-Turner D, Churchman ML, Harvey RC, Chen X, Kasap C, Yan C, Becksfort J, Finney RP, Teachey DT, Maude SL, Tse K, Moore R, Jones S, Mungall K, Birol I, Edmonson MN, Hu Y, Buetow KE, Chen IM, Carroll WL, Wei L, Ma J, Kleppe M, Levine RL, Garcia-Manero G, Larsen E, Shah NP, Devidas M, Reaman G, Smith M, Paugh SW, Evans WE, Grupp SA, Jeha S, Pui

CH, Gerhard DS, Downing JR, Willman CL, Loh M, Hunger SP, Marra MA, Mullighan CG. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell. 2012 Aug 14;22(2):153-66


De Braekeleer M, Guéganic N, Schifferli A, Tchinda J. A pediatric case of acute lymphoblastic leukemia with t(2;9)(q12;q34) (RANBP2/ABL1 fusion). Atlas Genet Cytogenet Oncol Haematol. 2017; 21(6):225-227.




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