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Products of haematopoiesis

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

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Products of haematopoiesis

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  1. Products of haematopoiesis

  2. 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

  3. Leukaemia Incidence CLL - Chronic Lymphocytic ALL - Acute Lymphocytic CML - Chronic Mylogenous AML - Acute Mylogenous

  4. Chromosome 9 Chromosome 22 13 bcr 14 c-abl 2-11 1 1 ALL breakpoint CML breakpoint bcr-abl Gene and Fusion Protein Tyrosine Kinases 9+ 9 Philadelphia chromosome t(9;22) Translocation 22 bcr bcr-abl fusion gene abl ALL p190bcr-abl CML p210bcr-abl

  5. 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

  6. 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

  7. 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)

  8. Molecular Mechanisms of AML1 action

  9. 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

  10. 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 treatment Olga 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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