Products of haematopoiesis

Leukaemia, the current hypothesis

• Defect in maturation of white blood cells-may involve a block in differentiation and/or a block in apoptosis

• Transformation events-Acquired genetic defect

• Initiating events unclear

• Chromosomal translocation implicated in many forms of leukaemia

Leukaemia Incidence

CLL - Chronic Lymphocytic

ALL - Acute Lymphocytic

CML - Chronic Mylogenous

AML - Acute Mylogenous

abl

t(9;22) Translocation

bcr-abl fusion gene

Philadelphia chromosome

9

22

bcr

p210 bcr-abl

p190 bcr-abl ALL

CML

Chromosome 22

1 13 14bcr

Chromosome 9

2-111c-abl

ALL breakpoint

CML breakpoint

bcr-abl Gene and Fusion Protein Tyrosine Kinases

9+

Targeted Therapy

• Imatinib Mesylate– Binds BCR-ABL kinase domain - -P– Frontline therapy for CML since 2001

• Second generation Kinase inhibitors– Dasatinib (Sprycel)– Nilotinib (Tasigna)

• Model for rational drug design

MLL

• Implicated in infant, childhood and adult leukaemia

• Implicated in myeloid , lymphoid and mixed lineage leukaemias

• 11q23 abnormalities (38 different translocations)

• t(4;11), t(9;11)

• Poor prognosis

AML1

• 21q

• AML1-ETO t(8;21)

• t(3;21)

• TEL-AML t(12;21)

• Loss of trans-activation domain critical to t(8;21) and t(3;21) abnormalities

• Inv (16)

Molecular Mechanisms of AML1 action

ALL-Primary cytogenetic subgroups

Cytogenetics Molecular FAB/ Incidence Clinical

t(4,11) MLL/AF-4 L1, L2

>90% infantile ALL

Often congenital, very high WBC worst prognosis

t(9,22) BCR-ABL (p190) L1, L2

5% paediatric ALL

25% adult ALL

Very high WBC count, expression of myeloid Antigens. TK activity v elevated

t(1,19) ELA/PBX L1, L2

5-6% of ALL

High WBC count, high serum LDH, low event-free survival

t(12,21) TEL/AML1 L1, L2

30% childhood ALL

25% ALL

Childhood disease (2-10yrs),

High cure rate with standard chemotherapy

t(8,14) MYC/IgH L3

3% ALL

Older children/young adults, high risk

>50 chromosomes

FISH for trisomy 21 L1, L2 Lower WBC count & serum LDH, age 2-10

Summary

• Molecular changes implicated in development of leukaemia

• Translocation is a major mechanism• CML - a paradigm for malignancy• Mutations in master genes such as AML1 and

MLL disrupt control of haematopoiesis leading to development of leukaemia

• Knowledge of molecular changes can influence diagnosis, prognosis and treatment

Further Reading• Chronic myeloid leukemia--advances in biology and new approaches to treatment.

Goldman JM, Melo JV

New England Journal of medicine 2003;349:1451-64

• Molecular characterization of acute myeloid leukemia and its impact on treatmentOlga Frankfurt, Jonathan D. Licht and Martin S. Tallman

Current Opinion in Oncology 2007;19:635-649

• Molecular Genetics of Acute Lymphoblastic Leukemia

Scott A. Armstrong and A. Thomas Look

Journal of Clinical Oncology 2005;23:6306-6315