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Polycythemia vera jak2
 

Polycythemia vera jak2

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abhishek rw

abhishek rw

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    Polycythemia vera jak2 Polycythemia vera jak2 Presentation Transcript

    • Polycythemia Vera .
    • Introduction
      • 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.
      • Bone marrow is typically hypercellular and exibits hyperplasia of myeloid, erythroid and megakaryocyte lineages.
    • Introduction
      • Alternative Names:
        • Primary polycythemia
        • Polycythemia rubra vera
        • Myeloproliferative disorder
        • Erythremia
        • Splenomegalic polycythemia
        • Vaquez's disease
        • Osler's disease
        • Polycythemia with chronic cyanosis
        • Myelopathic polycythemia
        • Erythrocytosis megalosplenica
        • Cryptogenic polycythemia
    • History
      • Vaquez, in 1892 first described persistent polycthemia.
      • Osler, in 1903 and 1908 clarified clinical picture of the disease.
      • Turk, in 1904, called attention to the occurrence of leukocytosis with erythrocytosis.
    • Revised WHO criteria for PCV
      • Major
        • Hgb >18.5 g/dl in men, 16.5 g/dL in women or evidence of increased red cell volume.
        • Presence of JAK2 V617F mutation
      • Minor
        • Hypercellular bone marrow biopsy with prominent erythroid, granulocytic, and megakaryocytic hyperplasia.
        • Serum erythropoietin level below normal reference range.
        • Endogenous erythroid colony formation in vitro
          • Using vitro culture techniques, there is formation of erythroid colonies in absence of added erythropoietin
      • Diagnosis requires presence of both major criteria and 1 minor or first major and 2 minor criteria.
    • .
      • 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.
      • 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.
    • 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)
    • Janus kinase 2 gene ( JAK2 )
      • The Janus kinase 2 gene ( JAK2 ) codes for a tyrosine kinase (JAK2) which is a transmembane receptors, important for signal transduction in hematopoietic cells.
      • Binding of JAK2 receptor by extracellular ligand causes receptor multimerization and activation by transphosphorylation.
      • Activated JAK2 then phosphorylates the cytoplasmic portion of the receptor and a cytoplasmic transcription factor, STAT5 (Signal Transducers and Activation of Transcription).
      • Phosphorylated STAT5 then translocate into the nucleus and initiate gene transcription, ultimately responsible for cell growth and differentiation.
    • .
    • JAK2 mutation
      • 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).
      • Mutation occurs in pseudokinase which is normally a negative regulator of kinase activity, resulting in continuously activated tyrosine kinase.
    • Involvement of Janus Kinases in Cytokine Signal Transduction (Panel A) and Structural Map of Janus Kinase 2 (Panel B)
    • JAK2 mutation
      • Mutation is exclusive to disorders of myeloid lineage and not observed in lymphoid neoplasms or solid tumors.
      • 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%).
    • .
      • Other cytogenetic abnormalities associated with PV are -
      • Trisomy 8 (+8)
      • Trisomy 9 (+9)
      • Deletion of long arm of chromosome 20 (20q-)
      • Deletion of long arm of chromosome 13 (13q-)
      • Deletion of long arm of chromosome 5 (5q-)
    • Thank you