MALIGNANCIES OF T

HE

HAEMAPOIETIC

STEM CELL

Haemapoietic Stem Cell are pluripotent and give rise to all of the haemopoietic cell under the action of cytokines.

Stem cell are identified by CD34 positivity and CD117 positivity .

CD117 is the receptor for stem cell factor

MYELOPROLIFERATIVE DISORDERSChronic Myeloid Leukemia Ph’ chromosome

Polycythaemia Rubra Vera Jak-2 mutation V617F 95% Jak-2 exon 12 mutations (6)

3%

Essential Thrombocythaemia Jak-2 mutation 50% CALR mutation 40% c-mpl mutation 5%

Primary Myelofibrosis Jak-2 mutation 50%

MYELODYSPLASTIC DISORDERSAbnormal looking haemopoitic cells with < 20% blasts in

marrow

Refractory cytopaenia with unilineage dysplasia

Refractory cytopaenias with multilineage dysplasias

Refractory anaemia with ringed sideroblasts

Refractory anaemia with excess of blasts.

High Risk MDS

Refractory Anaemia with Excess of Blasts

Secondary MDS from previous chemotherapy

Bad cytogenetics : p53 deletion Chr 17p Complex cytogenetics >/= 3 abnormalities

MYELODYSPLASTIC/ MYELOPROLIFERATIVE DISORDERS

Chronic myelomonocytic leukemia

Juvenile myelomoncytic leukemia.

Atypical CML

Myelodysplastic/myeloproliferative disorders unclassified

RARS with marked thrombocytosis

CHRONIC MYELOID LEUKEMIAChronic phase

Accelerated Phase

Acute Leukemia within 5 years.

TREATMENTAlkylating agentsInterferon-alphaAllogenic bone marrow transplant

Tyrosine Kinase inhibitors since 2003 Imatinib (Glivec) Dasatinib and nilotinib

SSS

ACUTE LEUKEMIASChildren 70% ALL 30% AML

Adults 70% AML 20% ALL 10% Mixed Lineage

AML1970’s French American British (FAB)

Morphology and Cytochemistry Myeloperoxidase (MPO) +ve MyeloblastsAlpha-Napthyl Acetate Esterase +ve for Monoblasts

M1 Immature myeloblastsM2 Some mature granulocytesM3 Acute Promyelocytic LeukemiaM4 Acute Myelomonocytic LeukemiaM5 Acute Monocytic LeukemiaM6 ErytholeukemiaM7 Megakaryoblastic Leukemia

M0 in 1988 : MPO –ve but myeloid marker CD13, CD33 positive by flow cytometry

M0 M1 M2

M3 M4 M5

M6 M7

AML RECURRENT CYTOGENETIC ABNORMALITIES

M2 with t(8;21) RUNX1-RUNX1T1M4 Eos inv 16 (p13.q22) CBFB-MYH11M3 t(15;17) PML-RARAM4/M5 t(9;11) MLLT3-MLL

AML with dysplasia t(6;9)AML with thrombocytosis inv(3)(q21;q26.2)M7 t(1,22)

ACUTE PROMYELOCYTCIC LEUKEMIAProne to DIC

Responds to All-trans retinoic Acid ATRA

Responds to low dose Arsenic

ALL RECURRENT CYTOGENETIC ABNORMALITIESB ALL t(9:22) t(12;21) TEL-AML1 or ETV6-RUNX1 t(1;19) t(v;11q23) MLL gene rearranged

GENE MUTATION STUDIESFLT-3 (Fms like tyrosine kinase-3)CEBPA (CCAAT enhancer-binder protein alpha) NM1 (Nucleophosmin)

RUNXWT1BAALCERGMN1

TREATMENTInduction therapies

ALL Vincristine, Dexamethasone, L-asparaginase

AML Daunorubacin 3 days, Arabinoside-C 7 days

Bone marrow transplant for high risk patients and relapsed patients

NOVEL AGENTSGemtuzamab Anti- CD33

Farnesyl transferase inhibitors

Hypomethylating agents GPC islands to activate tumour suppressor genes.

GENOMICS

Human Genome Project 1990-2003

$3 billion dollars

Multiple institutions China, France, Germany, Japan, Spain, Uk, USA

25,000 genes.

1.5% of genome are coding genes. 1% regulatory genes 97% non-coding sequences.

NEW GENERATION SEQUENCERSWhole genome sequencing $1,000 - $5,000 In a little over 24 hrs

TUMOURS STUDIEDAcute leukemiasBladderBreastHepatocellular carcinomaEosophagealGastricPancreaticProstate