Polycythemia vera jak2


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Polycythemia vera jak2

  1. 1. Polycythemia Vera .
  2. 2. Introduction <ul><li>Polycythemia vera is a chronic clonal myeloproliferative disorder characterized by increase in the number of red blood cells, total blood volume, and usually by leukocytosis, thrombocytosis, and splenomegaly. </li></ul><ul><li>Bone marrow is typically hypercellular and exibits hyperplasia of myeloid, erythroid and megakaryocyte lineages. </li></ul>
  3. 3. Introduction <ul><li>Alternative Names: </li></ul><ul><ul><li>Primary polycythemia </li></ul></ul><ul><ul><li>Polycythemia rubra vera </li></ul></ul><ul><ul><li>Myeloproliferative disorder </li></ul></ul><ul><ul><li>Erythremia </li></ul></ul><ul><ul><li>Splenomegalic polycythemia </li></ul></ul><ul><ul><li>Vaquez's disease </li></ul></ul><ul><ul><li>Osler's disease </li></ul></ul><ul><ul><li>Polycythemia with chronic cyanosis </li></ul></ul><ul><ul><li>Myelopathic polycythemia </li></ul></ul><ul><ul><li>Erythrocytosis megalosplenica </li></ul></ul><ul><ul><li>Cryptogenic polycythemia </li></ul></ul>
  4. 4. History <ul><li>Vaquez, in 1892 first described persistent polycthemia. </li></ul><ul><li>Osler, in 1903 and 1908 clarified clinical picture of the disease. </li></ul><ul><li>Turk, in 1904, called attention to the occurrence of leukocytosis with erythrocytosis. </li></ul>
  5. 5. Revised WHO criteria for PCV <ul><li>Major </li></ul><ul><ul><li>Hgb >18.5 g/dl in men, 16.5 g/dL in women or evidence of increased red cell volume. </li></ul></ul><ul><ul><li>Presence of JAK2 V617F mutation </li></ul></ul><ul><li>Minor </li></ul><ul><ul><li>Hypercellular bone marrow biopsy with prominent erythroid, granulocytic, and megakaryocytic hyperplasia. </li></ul></ul><ul><ul><li>Serum erythropoietin level below normal reference range. </li></ul></ul><ul><ul><li>Endogenous erythroid colony formation in vitro </li></ul></ul><ul><ul><ul><li>Using vitro culture techniques, there is formation of erythroid colonies in absence of added erythropoietin </li></ul></ul></ul><ul><li>Diagnosis requires presence of both major criteria and 1 minor or first major and 2 minor criteria. </li></ul>
  6. 6. . <ul><li>Of the various MPDs, there are the four common disorders, recognized as chronic myelogenous leukemia (CML), with its characteristic 9;22 translocation and BCR / ABL fusion protein, and other three non-CML MPDs – Polycythemia Vera, Essential Thrombocythemia and Chronic Idiopathic Myelofibrosis. </li></ul><ul><li>These common non-CML MPDs (PV, ET, CIMF) share a high incidence of the acquired point mutation in the JAK2 kinase, a cytoplasmic tyrosine kinase, important in hematopoetic cell proliferation. </li></ul>
  7. 7. Genetic abnormalities in CMPDs Disease Specific abnormalitis Reccuring, non specific cytogenetic abnormalities 1. Chronic myelogenous leukemia BCR / ABL, t(9;22) +Ph, +8, +9 2. Polycythemia Vera JAK2 V617F +8, +9, del(20q), del(13q) 3. Essential Thrombocythemia JAK2 V617F +8, del(13q) 4. Chronic Idiopathic Myelofibrosis. JAK2 V617F +8, del(20q), del(7q), del(13q) 5. Chronic Eosinophilic Leukemia +8, t(5;12), FIP1L1-PDGFRA 6. Systemic Mastocytosis FIP1L1-PDGFRA, KIDT816V 7. Chonic Neutrophilic Leukemia +8, +9, del(20q), del(11q14)
  8. 8. Janus kinase 2 gene ( JAK2 ) <ul><li>The Janus kinase 2 gene ( JAK2 ) codes for a tyrosine kinase (JAK2) which is a transmembane receptors, important for signal transduction in hematopoietic cells. </li></ul><ul><li>Binding of JAK2 receptor by extracellular ligand causes receptor multimerization and activation by transphosphorylation. </li></ul><ul><li>Activated JAK2 then phosphorylates the cytoplasmic portion of the receptor and a cytoplasmic transcription factor, STAT5 (Signal Transducers and Activation of Transcription). </li></ul><ul><li>Phosphorylated STAT5 then translocate into the nucleus and initiate gene transcription, ultimately responsible for cell growth and differentiation. </li></ul>
  9. 9. .
  10. 10. JAK2 mutation <ul><li>There is gain of function mutation on the short arm of chromosome 9, in which valine at position 617 of the Janus kinase 2 gene is replaced by phenylalanine (JAK2 V617F). </li></ul><ul><li>Mutation occurs in pseudokinase which is normally a negative regulator of kinase activity, resulting in continuously activated tyrosine kinase. </li></ul>
  11. 11. Involvement of Janus Kinases in Cytokine Signal Transduction (Panel A) and Structural Map of Janus Kinase 2 (Panel B)
  12. 12. JAK2 mutation <ul><li>Mutation is exclusive to disorders of myeloid lineage and not observed in lymphoid neoplasms or solid tumors. </li></ul><ul><li>This mutation appears to be present in upto 95% of PV patients. However, a significant proportion of patients with essential thrombocytosis and myelofibrosis also have the JAK2 mutation (about 30% – 50%). </li></ul>
  13. 13. . <ul><li>Other cytogenetic abnormalities associated with PV are - </li></ul><ul><li>Trisomy 8 (+8) </li></ul><ul><li>Trisomy 9 (+9) </li></ul><ul><li>Deletion of long arm of chromosome 20 (20q-) </li></ul><ul><li>Deletion of long arm of chromosome 13 (13q-) </li></ul><ul><li>Deletion of long arm of chromosome 5 (5q-) </li></ul>
  14. 14. Thank you