1. Molecular Medicine Dr Catherine Flynn Consultant Haematologist St James’s Hospital October 22 nd 2009

2. Molecules DNA mRNA Protein Transcription Translation

3. Cell Cycle Stem Cells/ Quiescence Do different cancer stem cells have the same Achilles' heel ???

4. Molecules… at the bench….. DNA mRNA Protein Transcription Translation Micro array SNP Proteomics Short Inhibitory RNA

5. ………….To The Bedside What is the biology of acute myeloid leukaemia? What is the best treatment for chronic myeloid leukaemia? Which Patient should have a transplant?

6. Haematopoiesis

7. Morphology Karyotype Molecular Diagnostics Leukaemia Diagnosis

8. Modify Diagnosis Counsel patient and family better re prognosis Recommend specific treatment DNA mRNA Protein Symptoms and SignsLaboratory Findings

9. Haematopoiesis

10. Leukaemia An Acquired Cancer –(rare inherited leukaemias reported) Differentiation Arrest Mutations disrupt genes controlling Proliferation uncontrolled growth of an immature clone of cells

11. Hematology 2007;2007:509-520 Model of leukaemogenesis with two cooperating classes of mutations

12. Risk Factors?

13. Frohling S and Dohner H. N Engl J Med 2008;359:722-734 Structure of a Human Chromosome

14. Frohling S and Dohner H. N Engl J Med 2008;359:722-734 Chromosomal Abnormalities in Human Cancer

15. Acute Myeloid Leukaemia Abnormalities seen in at least 50 %of cases Karyotype is of major prognostic significance Used in planning treatment

16. Acute Myeloid Leukaemia FavourableIntermediatePoor t(8;21) AML1/ETO Normal Karyotype Complex karyotype ( >3) inv(16)inv(3) or t(3;3) t(15;17)

17. Survival from CR by MRC Cytogenetic Risk Group 100 75 50 25 0 Favourable Intermediate Poor 012345 Years from randomisation 68% 44% 18% 2P <0.00001 % still alive Similar results in SWOG/EGOG study (Slovak et al, 2000 ) and CALGB (Byrd et al, 2002)

18. Karyotypic Normal AML "Should I recommend an allogeneic stem- cell transplant, or not?" Graft versus Leukaemia/ Potential Cure Toxicity/Mortality

19. Copyright ©2007 American Society of Hematology. Copyright restrictions may apply. Maslak, P. ASH Image Bank 2007;2007:7-00028 Figure 2. Cells with multiple Auer rods (arrow) may be appreciated Acute Promyelocytic Leukaemia (APML)

20. Copyright ©2009 American Society of Hematology. Copyright restrictions may apply. Lazarchick, J. ASH Image Bank 2009;2009:8-00163 Figure 1. A "faggot" cell present on the peripheral smear from a patient with acute promelocytic leukemia is shown

21. Myeloid Maturation Differentiation Arrest in APML

22. Licht J. N Engl J Med 2009;360:928-930 Countering PML/RARα with All-trans Retinoic Acid RARα PML Encourages Self Renewal Blocks differentiation

23. The karyotype of patients with Acute Myeloid Leukaemia can be helpful. PML/RARα translocation is found in AML called acute promyelocytic leukaemia (APML). This fusion protein………. A.is responsible for the response to Retinoic Acid/ATRA B.is caused by a translocation between chromosomes 15 and 19 C.is associated with a poor outcome D.predicts age of onset E.is only seen in the elderly

24. Chronic Myeloid Leukaemia A Paradigm for Malignancy

25. 23451 7891010 11126 131415161718 The Philadelphia Chromosome

26. Philadephia Chromosome

27. The Ideal Target for Molecular Therapy Present in the majority of patients with the disease Determined to be the causative abnormality Has unique activity that is - Required for disease induction - Dispensable for normal cellular function Courtesy of BJ Druker, MD

28. Bcr-Abl as a Therapeutic Target for CML Bcr-Abl is detected in 95% of patients with CML Bcr-Abl is the causative abnormality of CML Bcr-Abl tyrosine kinase is constitutively activated intracellularly Tyrosine kinase activity is required for CML cell function Abl null mice are viable

29. (From Novartis Pharma) (C 30 H 35 N 7 SO 4 ) N N N H N H N N N O N Imatinib mesylate (STI571 - Glivec ® )

30. Goldman J and Melo J. N Engl J Med 2001;344:1084-1086 Mechanism of Action of STI571/Glevec/Imatinib

31. Goldman, J. M. et al. N Engl J Med 2003;349:1451-1464 Signal-Transduction Pathways Affected by BCR-ABL

32. Druker B et al. N Engl J Med 2006;355:2408-2417 Kaplan-Meier Estimates of the Cumulative Best Response to Initial Imatinib Therapy

33. Chronic Myeloid Leukaemia Janet Rowley Receives Presdential Medal of Freedom August 2009 Chronic Myeloid Leukaemia

34. STI 571/Gleevec/Imatinib was developed in the late 1990s to treat CML. Its mode of action is in ……… A.DNA methylation B.Cell cycle arrest C.Tyrosine kinase inhibitor D.Protein destruction E.Inhibition of cell differentiation