MALIGNANCIES OF THE 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 DISORDERS Chronic 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 DISORDERS Abnormal 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 LEUKEMIA Chronic phase Accelerated Phase Acute Leukemia within 5 years.

TREATMENT Alkylating agents Interferon-alpha Allogenic bone marrow transplant Tyrosine Kinase inhibitors since 2003 Imatinib (Glivec) Dasatinib and nilotinib

SSS

ACUTE LEUKEMIAS Children 70% ALL 30% AML Adults 70% AML 20% ALL 10% Mixed Lineage

AML 1970’s French American British (FAB) Morphology and Cytochemistry Myeloperoxidase (MPO) +ve Myeloblasts Alpha-Napthyl Acetate Esterase +ve for Monoblasts M1 Immature myeloblasts M2 Some mature granulocytes M3 Acute Promyelocytic Leukemia M4 Acute Myelomonocytic Leukemia M5 Acute Monocytic Leukemia M6 Erytholeukemia M7 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-RUNX1T1 M4 Eos inv 16 (p13.q22) CBFB-MYH11 M3 t(15;17) PML-RARA M4/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 LEUKEMIA Prone to DIC Responds to All-trans retinoic Acid ATRA Responds to low dose Arsenic

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

GENE MUTATION STUDIES FLT-3 (Fms like tyrosine kinase-3) CEBPA (CCAAT enhancer-binder protein alpha) NM1 (Nucleophosmin) RUNX WT1 BAALC ERG MN1

TREATMENT Induction 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 AGENTS Gemtuzamab Anti- CD33 Farnesyl transferase inhibitors Hypomethylating agents GPC islands to activate tumour suppressor genes.

GENOMICS Human Genome Project $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 SEQUENCERS Whole genome sequencing $1,000 - $5,000 In a little over 24 hrs

TUMOURS STUDIED Acute leukemias Bladder Breast Hepatocellular carcinoma Eosophageal Gastric Pancreatic Prostate