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
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