pok (poz and krüppel) protein family -...
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POK (POZ and Krüppel) protein familyPOZPOZ11 673673PLZFPLZF APLAPLZnZn++++ZnZn++++ZnZn++++ZnZn++++ZnZn++++ZnZn++++ZnZn++++ZnZn++++ZnZn++++
NHLNHLPOZPOZ11 706706BCL-6BCL-6 ZnZn++++ZnZn++++ZnZn++++ZnZn++++ZnZn++++ZnZn++++
POZPOZ11 543543POKEMONPOKEMON ZnZn++++ZnZn++++ZnZn++++ZnZn++++
-More than 40 POK proteins identified in the humangenome-Amino terminal POZ domain, homo- and hetero-dimerization and recruitment of histone deacetylases(HDACs)-C-terminal zinc fingers mediate specific DNArecognition and binding
POKEMONPOK Erythroid Myeloid Ontogenic Factor
-Synonyms-LRF (Lymphoma–Related Factor)-OCZF (OsteoClast–derived Zinc Finger)-FBI-1 (Factor that binds IST, HIV inducer of short transcripts)
-Critical and pleiotropic function in cellulardifferentiation-Can physically interact with BCL6-Zbtb7 (synonym name of gene in mouse) results inembryonic lethality and impaired cellular differentiationin multiple tissues, including the B-cell compartment-Zbtb7 genes reside on chromosome 19p13.3, hotspotfor chromosomal translocations
-Pokemon is a specific ARF transcriptionalrepressor
-Loss of Pokemon causes aberrant ARF up-regulation, resulting in premature senescence andunresponsiveness to oncogenic stimuli
-First ARF-specific transcriptional repressor to beidentified
Nature. 2005 Jan 20;433(7023):278-85
Oncogenic role of Pokemon in vivo
-Pokemon–null embryos demonstrate defects in B–celldevelopment
-Pokemon is expressed in the germinal center of lymphoidtissues and interacts with BCL6
-Pokemon is highly expressed in T-cell lymphomas
-Transgenic mouse model in which Pokemon is over-expressedin immature T and B cells using the LckEu enhancer/promotertransgenic construct
Reactive Tonsil (Human)
40x 100x
400x 400x
YEAR
1211109876543210
Cum
ulat
ive
Sur
viva
l
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.1
0.0
GCB: N=28, 11 censored
non-GCN: N=60, 22 censored
p=0.68
CD10
+
-BCL -6
-
+
GCB, n=20
MUM1
+
-
Non -GC, n=32
Non -GC, n=28
GCB, n=8
CD10
+
-BCL -6
-
+
GCB, n=20
MUM1
+
-
Non -GC, n=32
Non -GC, n=28
GCB, n=8
A.B.
YEAR
1211109876543210
Cum
ulat
ive
Sur
viva
l
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.1
0.0
GCB: N=28, 11 censored
non-GCN: N=60, 22 censored
p=0.68
CD10
+
-BCL -6
-
+
GCB, n=20
MUM1
+
-
Non -GC, n=32
Non -GC, n=28
GCB, n=8
CD10
+
-BCL -6
-
+
GCB, n=20
MUM1
+
-
Non -GC, n=32
Non -GC, n=28
GCB, n=8
YEAR
1211109876543210
Cum
ulat
ive
Sur
viva
l
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.1
0.0
GCB: N=28, 11 censored
non-GCN: N=60, 22 censored
p=0.68
CD10
+
-BCL -6
-
+
GCB, n=20
MUM1
+
-
Non -GC, n=32
Non -GC, n=28
GCB, n=8
CD10
+
-BCL -6
-
+
GCB, n=20
MUM1
+
-
Non -GC, n=32
Non -GC, n=28
GCB, n=8
CD10
+
-BCL -6
-
+
GCB, n=20
MUM1
+
-
Non -GC, n=32
Non -GC, n=28
GCB, n=8
CD10
+
-BCL -6
-
+
GCB, n=20
MUM1
+
-
Non -GC, n=32
Non -GC, n=28
GCB, n=8
A.B.
Blood. 2005 Aug 9; [Epub ahead of print]
-21/88 pts 100% concordance with original and relapsed/ref biopsy-BCL6 loss in 5 cases; MUM1 loss in 4 cases -17/88 cases profiled by gene expression, 90% concordance with IHC-33 cases of DLBCL at diagnosis profiled, 86% concordance with IHC
-Mutations in Arf/P53 pathway relatively rare in DLBCLcompared to solid tumors; both arf/p53 mutant micecommonly develop lymphomas
Blood 101: 1220-35, 2003; Nature 356:215-221, 1992; Cancer Res 59:2217-22, 1999
-Real-time RT-PCR of DLBCL cases showed high Pokemongene expression generally correlated with low expressionof p14Arf
-Pokemon is over-expressed in colon and bladder cancers;Arf/P53 pathway is lost; likely Pokemon has multipleadditional target genes
Kaiso, binds to methylated DNA sequences, enhancesrepression of target genes, Mol Cell 12:723-34, 2003
Substrate targeting of cullin-based E3 ligase complexes, role inprotein ubiquitination Embo 23:1681-87, 2004
-Genetic evidence directly linking Pokemon with humancancer lacking
-chromosomal translocations, mutations of the Pokemon locus-however, genomic locus of Pokemon gene, 19p13.3 frequently mutated-t(14;19)(q32;p13.3) more common cryptic translocations with IgH Cancer Res 62:5523-27, 2002
-Pokemon up-regulation due to aberrant activation ofupstream regulatory pathways
-Pokemon (FBI-1) induced upon fibronectin mediated beta1-integrin ligation in precursor B leukemia cells Blood 101:1118-27, 2003
84
2110Others
3102NK/T
43121912PTCL
172510Lymphoblastic
11740Angioimmunoblastic
8620ALCL
TotalStrongModerateNegative
WHO Classification of Hodgkin Lymphoma
Nodular lymphocyte-predominant Hodgkinlymphoma (NLPHL)
Classical Hodgkin lymphoma (cHL)Nodular sclerosisMixed cellularityLymphocyte-richLymphocyte-depleted
50Total
306195cHL (NS)
201820NLPHL
TotalStrongModerateNegative
POK Proteins-Important in embryonic development, differentiation, and oncogenesis
-Plzf (Promyelocytic Leukemia Zinc Finger)null mice, severe defects in limb development and germ cell maintenance
Nat Genet 25:166-172, 2000; Nat Genet 36:653-659, 2004Nature 436:277-81, 2005
-Th-POK (T-helper-inducing POZ/Krüppel-like factor),cKroxmaster regulator of T-cell lineage commitment
Nature 433:826-833, 2005; Nat Immunol 8:761-66, 2005
-Involved in chromosomal translocations in APL and NHLNat Genet 16:161-170, 1997; PNAS 94:10255-60, 1997
-HIC1 (Hypermethylated in cancer-1)hypermethylated and transcriptionally silent in human tumorsheterozygous mice develop spontaneous malignant tumors
Nat Genet 33:197-202, 2003
T CellT Cell
B CellB Cell
MonocyteMonocyte
GranulocyteGranulocyte
MegakaryocyteMegakaryocyte
ErythrocyteErythrocyte
CLPCLP
CMPCMP
GMPGMP
MEPMEP
Pro-TPro-T
Pro-BPro-B
????
-Functional networks and cross-talk likely more dynamic andcomplicated than anticipated
-POK and POZ/BTB-containing protein families, > 100 proteins-POZ/BTB domain, single copy in proteins that also contain oneor two other domain types
zinc finger (POK proteins)BACK-kelchvoltage-gated potassium channel T1MATH domains
-Multitude of potential interaction partners for POK proteins expected
-Great diversity in cellular functions beyond simple target-generepression
-Attractive therapeutic target, essential role in oncogenictransformation
Nature. 2005 Aug 11;436(7052):807-11
Diffuse Large B-cell Lymphomas (DLBCL) WithTerminally Differentiated B-cell Phenotype
Plasmablastic Lymphomas (PBLs)PBL of oral mucosa typePBL with plasmacytic differentiation
!HHV-8-Positive PBLs
Primary Effusion Lymphoma (PEL)Extra-cavitary variant of PEL or KSHV-positive solid lymphomaGerminotropic Lymphoproliferative disorder (GLD)**Plasmablastic lymphoma associated with multicentric Castleman disease*/**
!Extramedullary plasmablastic tumours secondary to plasma cell neoplasms
DLBCL expressing ALK!Differential Diagnosis*DLBCL with secretory differentiationPyothorax-associated lymphomaAtypical Burkitt lymphoma with plasmacytoid differentiation
Curr Oncol Rep. 2005 Sep;7(5):357-63
CD138CD138 MIB1MIB1 EBER1EBER1
PET-L PET-R
BM-H&E
H&E HHV8
ALK
Diffuse Large B-cell Lymphomas (DLBCL) With TerminallyDifferentiated B-cell Phenotype
-Rare tumorsEither EBV+, HHV8+, or bothImmunocompromised and immunocompetent
-Clinicopathologic spectrum of tumors with plasma cell orterminal B-cell differentiation
Indolent and localizedWidely disseminated with extensive bony metastasis and aggressive clinical course
-No uniform standard treatment except for HAART inHIV-positive patients
-Distinguishing from multiple myeloma with plasmablasticfeatures, most impact in terms of clinical andtherapeutic management
Diffuse Large B-cell Lymphomas (DLBCL) With TerminallyDifferentiated B-cell Phenotype
-Challenge to investigate the role of recently described molecules interms of mechanisms of tumorigenesisand potential therapeutic targets
BLIMP1 (B-lymphocyte-induced maturation protein 1)XBP1 (X-box-binding protein 1)PAX5 (paired box protein 5)BCL-6 (B-cell lymphoma-6)MTA3 (metastasis-associated 1 family, member 3)
Tissue Inhibitor of Metalloproteinase 1 (TIMP-1)Repress GC markers: CD10, BCL6, PAX5Up-regulate CD138, MUM1, XBP1, CD44Blood. 2005 Feb 15;105(4):1660-8. Epub 2004 Oct 12
Tumor Protein D52 (TPD52)Blood. 2005 Apr 1;105(7):2812-20. Epub 2004 Dec 2
AcknowledgmentsCancer Biology and Genetics Program Department of MedicineDepartment of Pathology Craig MoskowitzTakahiro Maeda Andrew ZelenetzRobbin Hobbs Terun KewalramaniTaha Merghoub Paul HamlinIlhem Guernah Simone Lessac-ChenenArthur Zelenent Jane HouldsworthCarlos Cordon-Cardo Adam OlshenPier Paolo Pandolfi Raju Chaganti
Stephen NimerCarol Portlock
Cold Spring Harbor LaboratoryMike HemannAnka BricAndreas HerbstJonas NilssonJohn ClevelandWilliam TanseyScott Lowe