MALIGNANCIE

S OF

THE

HAEMAPOIE

TIC S

TEM C

ELL

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 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 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