Polycythemia VeraPolycythemia Vera

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IntroductionIntroduction

Polycythemia vera is a chronic clonal Polycythemia vera is a chronic clonal myeloproliferative disorder characterized myeloproliferative disorder characterized by increase in the number of red blood by increase in the number of red blood cells, total blood volume, and usually by cells, total blood volume, and usually by leukocytosis, thrombocytosis, and leukocytosis, thrombocytosis, and splenomegaly.splenomegaly.

Bone marrow is typically hypercellular and Bone marrow is typically hypercellular and exibits hyperplasia of myeloid, erythroid exibits hyperplasia of myeloid, erythroid and megakaryocyte lineages. and megakaryocyte lineages.

IntroductionIntroduction Alternative Names:Alternative Names:

Primary polycythemia Primary polycythemia Polycythemia rubra veraPolycythemia rubra vera Myeloproliferative disorderMyeloproliferative disorder ErythremiaErythremia Splenomegalic polycythemiaSplenomegalic polycythemia Vaquez's diseaseVaquez's disease Osler's diseaseOsler's disease Polycythemia with chronic cyanosisPolycythemia with chronic cyanosis Myelopathic polycythemiaMyelopathic polycythemia Erythrocytosis megalosplenicaErythrocytosis megalosplenica Cryptogenic polycythemia Cryptogenic polycythemia

HistoryHistory

Vaquez, in 1892 first described persistent Vaquez, in 1892 first described persistent polycthemia.polycthemia.

Osler, in 1903 and 1908 clarified clinical Osler, in 1903 and 1908 clarified clinical picture of the disease.picture of the disease.

Turk, in 1904, called attention to the Turk, in 1904, called attention to the occurrence of leukocytosis with occurrence of leukocytosis with erythrocytosis.erythrocytosis.

Revised WHO criteria for PCVRevised WHO criteria for PCV• MajorMajor

– Hgb >18.5 g/dl in men, 16.5 g/dL in women or evidence of Hgb >18.5 g/dl in men, 16.5 g/dL in women or evidence of increased red cell volume.increased red cell volume.

– Presence of JAK2 V617F mutationPresence of JAK2 V617F mutation• MinorMinor

– Hypercellular bone marrow biopsy with prominent erythroid, Hypercellular bone marrow biopsy with prominent erythroid, granulocytic, and megakaryocytic hyperplasia.granulocytic, and megakaryocytic hyperplasia.

– Serum erythropoietin level below normal reference range.Serum erythropoietin level below normal reference range.– Endogenous erythroid colony formation in vitroEndogenous erythroid colony formation in vitro

• Using vitro culture techniques, there is formation of erythroid Using vitro culture techniques, there is formation of erythroid colonies in absence of added erythropoietincolonies in absence of added erythropoietin

• Diagnosis requires presence of both major criteria and 1 minor or Diagnosis requires presence of both major criteria and 1 minor or first major and 2 minor criteria.first major and 2 minor criteria.

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Of the various MPDs, there are the four common Of the various MPDs, there are the four common disorders, recognized as chronic myelogenous disorders, recognized as chronic myelogenous leukemia (CML), with its characteristic 9;22 leukemia (CML), with its characteristic 9;22 translocation and BCR / ABL fusion protein, and translocation and BCR / ABL fusion protein, and other three non-CML MPDs – Polycythemia other three non-CML MPDs – Polycythemia Vera, Essential Thrombocythemia and Chronic Vera, Essential Thrombocythemia and Chronic Idiopathic Myelofibrosis.Idiopathic Myelofibrosis.

These common non-CML MPDs (PV, ET, CIMF) These common non-CML MPDs (PV, ET, CIMF) share a high incidence of the acquired point share a high incidence of the acquired point mutation in the JAK2 kinase, a cytoplasmic mutation in the JAK2 kinase, a cytoplasmic tyrosine kinase, important in hematopoetic cell tyrosine kinase, important in hematopoetic cell proliferation.proliferation.

Genetic abnormalities in CMPDsGenetic 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 (Janus kinase 2 gene (JAK2JAK2)) The Janus kinase 2 gene (The Janus kinase 2 gene (JAK2JAK2) codes for a tyrosine ) codes for a tyrosine

kinase (JAK2) which is a transmembane receptors, kinase (JAK2) which is a transmembane receptors, important for signal transduction in hematopoietic cells. important for signal transduction in hematopoietic cells.

Binding of JAK2 receptor by extracellular ligand causes Binding of JAK2 receptor by extracellular ligand causes receptor multimerization and activation by receptor multimerization and activation by transphosphorylation. transphosphorylation.

Activated JAK2 then phosphorylates the cytoplasmic Activated JAK2 then phosphorylates the cytoplasmic portion of the receptor and a cytoplasmic transcription portion of the receptor and a cytoplasmic transcription factor, STAT5 (Signal Transducers and Activation of factor, STAT5 (Signal Transducers and Activation of Transcription).Transcription).

Phosphorylated STAT5 then translocate into the nucleus Phosphorylated STAT5 then translocate into the nucleus and initiate gene transcription, ultimately responsible for and initiate gene transcription, ultimately responsible for cell growth and differentiation.cell growth and differentiation.

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JAK2 mutationJAK2 mutation• There is gain of function mutation on the short There is gain of function mutation on the short

arm of chromosome 9, in which valine at position arm of chromosome 9, in which valine at position 617 of the Janus kinase 2 gene is replaced by 617 of the Janus kinase 2 gene is replaced by phenylalanine (JAK2 V617F).phenylalanine (JAK2 V617F).

• Mutation occurs in pseudokinase which is Mutation occurs in pseudokinase which is normally a negative regulator of kinase activity, normally a negative regulator of kinase activity, resulting in continuously activated tyrosine resulting in continuously activated tyrosine kinase.kinase.

Involvement of Janus Kinases in Cytokine Signal Transduction (Panel A)Involvement of Janus Kinases in Cytokine Signal Transduction (Panel A)and Structural Map of Janus Kinase 2 (Panel B)and Structural Map of Janus Kinase 2 (Panel B)

JAK2 mutationJAK2 mutation

• Mutation is exclusive to disorders of Mutation is exclusive to disorders of myeloid lineage and not observed in myeloid lineage and not observed in lymphoid neoplasms or solid tumors.lymphoid neoplasms or solid tumors.

• This mutation appears to be present in This mutation appears to be present in upto 95% of PV patients. However, a upto 95% of PV patients. However, a significant proportion of patients with significant proportion of patients with essential thrombocytosis and essential thrombocytosis and myelofibrosis also have the JAK2 mutation myelofibrosis also have the JAK2 mutation (about 30% – 50%).(about 30% – 50%).

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Other cytogenetic abnormalities Other cytogenetic abnormalities associated with PV are - associated with PV are -

1.1. Trisomy 8 (+8)Trisomy 8 (+8)

2.2. Trisomy 9 (+9)Trisomy 9 (+9)

3.3. Deletion of long arm of chromosome 20 Deletion of long arm of chromosome 20 (20q-)(20q-)

4.4. Deletion of long arm of chromosome 13 Deletion of long arm of chromosome 13 (13q-)(13q-)

5.5. Deletion of long arm of chromosome 5 Deletion of long arm of chromosome 5 (5q-)(5q-)

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