Malignant hematopoiesis (1) Myeloproliferative disorders Emanuel Nečas

1. Malignant hematopoiesis (1) Myeloproliferative disorders Emanuel Nečas necas@cesnet.cz

2. Introduction

3. Myelopoiesis and Lymphopoiesis

4. Myelopoiesis and Lymphopoiesis • myeloid cells (erythropoiesis, granulocytopoiesis, monocytopoiesis, thrombocytopoiesis _ megakaryocytes) • lymphoid cells (B-lymphopoiesis, T-lymphopoiesis, NK-lymphopoiesis)

5. Myeloproliferative disorders Lymfoproliferative disorders

6. Myeloproliferative disorders - chronic - acute Lymfoproliferative disorders - chronic - acute

7. Lymphoproliferative diseasescan also have a form of a solid tumor,a lymphoma.Though seemingly localized to a lymphoid tissue outside the bone marrow, it is considered to be a systemic disease involving (infiltrating) the bone marrow regularly.

8. A single leukemic stem cells starts the disease. The disease then spreads throughout the body.

9. Malignant hematopoiesis is usually monoclonal is usually systemic

10. Normal hematopoiesis is polyclonal

11. Origin of the normal polyclonal hematopoiesis is in embryogenesis A B B C D E F F G H

12. Malignant hematopoiesis is monoclonal(examples: acute myeloid leukemia; AML)

13. XpXm XpXm XpXm female somatic cells Embryogenesis random X-inactivation Xm Xp Clonal Event Xm Xm Xp Xp Xm Xm Xm Xm Xp Xp Xp Xp Xp Xp Xp Xp Xp Xp

14. Malignant monoclonal hematopoiesis is caused by mutations (F´cell clone) A B B C D E F´ F G H

15. Treatment eliminates or supresses the malignant clone and normal polyclonal hematopoiesis usually resumes Possible therapy outcomes • remission • successful treatment (complete remission) • residual disease • relaps

16. A pathological dominant clone may start from a mutated hematopoietic stem cell but not necessarily. A mutated progenitor cell may be a source of a dominant malignant clone as well.

18. Normal bone marrow and CML, AML, CLL CML AML CLL

19. Chronic myeloproliferative disorders

20. Chronic myeloproliferative diseases • Myelodysplastic syndrome (MDS) • Polycythemia vera rubra • Chronicmyeloidleukemia(CML) • Essentialthrobocythemia • Idiopathic Myelofibrosis/orAgnogenic Myeloid Metaplasia • Chroniclymphocyticleukemia (CLL) …islymphoproliferativedisease

21. Myeloproliferative Disorders

22. (Chronic) Myeloproliferative Disorders – common features • Acquired mutation in a hematopoietic stem cell • Clonal hematopoiesis • Proliferation of granulocytes, red cells and/or platelets • Splenomegaly (variable) • Bone marrow fibrosis (variable)

23. Myelodysplastic syndrome (MDS)

25. Myelodysplastic syndrome (MDS) MDS is a myeloproliferativedisease, used to becalled „preleukemia“ It has severalforms. Thereisdecreasednumberof „myeloid“ cell in theblood (anemia, granulocytopenia, thrombocytopenia = pancytopenia)

26. Normal bone marrow Dysplastic bone marrow Normal and dysplastic (MDS) bone marrow

27. Dysplastic bone marrow in the RAEB (refractory anemia with excess of blasts) a form of the MDS

30. MDS – etiopathogenesis and conversion into AML Altered immune response Altered marrow stroma Altered cytokine response Radiation Oxidative stress Increased apoptosis Clonal myelo- poiesis Stem cell mutation Clonal evolution Age AML Ineffective haemopoiesis T-cell attack Chemicals Additional mutations/epigenetic changes

33. Polycythemia vera rubra („primary polycythemia“,Disease Vasquez-Osler)

34. Polycythemias Hct 43% 53% 53%

35. Polycythemia Vera • An acquired mutation of hematopoietic single stem cell • The nature of the disease causing mutation not known till 2005 – most cases have mutation in the JAK2 tyrosinkinase

36. Polycythemia vera, Essential trombocythemia, Idiopathic myeolofibrosis

37. Incidence of Polycythemia Vera Frequency, % Age

38. Phlebotomy Chlorambucil 32P Cumulative Survival on Study (PV) 1.0 0.8 0.6 0.4 0.2 0.0 Cumulative survival 0 100 200 300 400 500 600 700 800 Time in weeks

39. Polycythemia vera causes of death(expressed as percentage)

40. Sensitivityof BFU-EtoEpo 100% PV (EEC) 75% PFCP 50% Normal EEC 25% 0% 0 30 60 125 250 3000 EPO (mU/ml)

41. Essential thrombocytemia

42. Essential Thrombocythemia • Platelet count in excess of 600,000 permm3 • Marked megakaryocytic hyperplasia • Abundant platelet clumps

43. Essential Thrombocythemia • No cytogenetic abnormalities • Splenomegaly seen in fewer than 50% • Morbidity: Thrombotic and/or bleeding problems

44. Essential Thrombocythemia • No cytogenetic abnormalities • The same mutation in the JAK2 kinase as causes Polycythemia vera is present in some patients

45. Idiopathic Myelofibrosis/Agnogenic Myeloid Metaplasia

46. Must exclude other causes of bone marrow fibrosis “Spent phase” of PV or ET CML Hairy cell leukemia Lymphoma Metastatic cancer Idiopathic Myelofibrosis/Agnogenic Myeloid Metaplasia (AMM)

47. Chronic myleoid leukemia (CML)

48. Proliferation of granulocytes All stages of granulocyte maturation in peripheral blood Platelets may be elevated Polycythemia is rare Splenomegaly, may be massive Invariable transformation to acute leukemia Chonic Myelogenous Leukemia