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 bcr Chromosome c-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 CytogeneticsMolecularFAB/ IncidenceClinical t(4,11)MLL/AF-4L1, 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/PBXL1, L2 5-6% of ALL High WBC count, high serum LDH, low event-free survival t(12,21)TEL/AML1L1, L2 30% childhood ALL 25% ALL Childhood disease (2-10yrs), High cure rate with standard chemotherapy t(8,14)MYC/IgHL3 3% ALL Older children/young adults, high risk >50 chromosomes FISH for trisomy 21L1, L2Lower 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: 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: Molecular Genetics of Acute Lymphoblastic Leukemia Scott A. Armstrong and A. Thomas Look Journal of Clinical Oncology 2005;23: