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MPNs; Definition, Types of MPN Mutations, Aetiology, Clinical features, CML
Myeloproliferative neoplasms (MPNs) are clonal hematopoietic disorders resulting in the overproduction of myeloid lineages, including granulocytes, erythrocytes, and megakaryocytes, often associated with mutations such as JAK2. The document outlines various types of MPNs, specifically Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Myelofibrosis (MF), their clinical features, diagnostic criteria, and potential treatment options. Chronic Myeloid Leukemia (CML) is also discussed, highlighting the presence of the Philadelphia chromosome as a significant marker for diagnosis.
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MPNs; Definition, Types of MPN Mutations, Aetiology, Clinical features, CML
- 1.
- 2. Objectives • Definition ofMPN • Types of MPN • Mutations of MPN • Aetiology of MPN • Clinical features of MPN • CML and Philadelphia Chromosome • Definition of each type
- 3. List of Contents: •Definition • Types • PV • ET • MF • CML and Philadelphia Chromosome • Summary or conclusion • Question
- 4. Myeloproliferative Neoplasms MPNs (PV,ET, MF) • Clonal hematopoeitic disorders • Proliferation of one or more of myeloid lineages: – Granulocytic – Erythroid – Megakaryocytic
- 5. Aetiology Single acquired mutationof the cytoplasmic tyrosine kinase Janus-associated kinase 2 (JAK2) (Val 617 Phe). JAK2 mutation in: All patients with Polycythemia Vera and in 50% of those with Essential Thrombocythemia and Idiopathic Myelofibrosis
- 6. In MPN • Thereare Relatively normal maturation of the cells • Each type closely related to each other. • Evolution from one entity into another occurs during the course of the disease. • Special risk of leukemic transformation
- 7. Activation of JAK2 Proliferationof cell Receptor Hemopoietic growth factors JAK2 Protein Progenit or cell RBC Granulocyte Megakaryocyte Platelet NORMALLY
- 8. Activation of JAK2 &Proliferation of the cell Without growth factor Receptor Hemopoietic growth factors JAK2 Protein MUTATION Progenit or cell RBC Granulocyte Megakaryocyte Platelet JAK2 Mutation
- 9. Bone marrow stemcell Clonal abnormality Granulocyte precursors Red cell precursors Megakaryocytes Reactive fibrosis Essential thrombocytosis (ET) Polycythaemia vera (PV) Myelofibrosis AML Chronic myeloid leukemia 70% 10% 10% 30%
- 10. Polycythemia Vera Definition ofpolycythemia Its increase in the Hb concentration above the upper limits of normal range for the patient age and sex. • Raised packed cell volume (PCV) • Male > 52% (normally 40-52%) • Female > 48% (normally 36-48%) Classification • Absolute(Total red cell volume & total plasma volume increased » Polycythaemia vera » Secondary polycythaemia » Idiopathic erythrocytosis • Apparent or relative
- 11. Polycythemia Vera Polycythemia Verais a clonal stem cell disorder characterized by increased red cell production • Abnormal clones behave autonomous • Same abnormal stem cell give rise to granulocytes and platelets
- 12. Clinical features - Theincreased PCV leads to: • an increased blood viscosity, Hyperviscosity • abnormal platelet–endothelial contact increase thrombotic risk. • Neurological features Over and above the consequences of occlusive vascular lesions, the sluggish cerebral blood flow secondary to the increased PCV is thought to underlie features such as headaches, drowsiness, insomnia, amnesia, tinnitus, vertigo, chorea and even depression. • Transient visual disturbances also occur.
- 13. Polycythemia Vera Laboratory featuresand morphology • Hb, PCV (HCT), and Red cell mass increased • Increased neutrophils and platelets • NAP score normal or increased • Serum uric acid high (gout) • Circulating erythroid precursors (nucleated RBC) • Hypercellular bone marrow • Low serum erythropoietin
- 14. Secondary polycythemia • Causedby compensatory erythropoietin ↑ in - high altitudes - pulmonary disease and alveolar hypoventilation - cardiovascular disease. - increased affinity Hb (familial polycythemia) - heavy cigarette smoking. • Caused by inappropriate erythropoietin increase in - renal disease. - tumours such as uterine fibroma, hepatocellular carcinoma, cerebellar haemangioma.
- 15. Relative polycythemia causes • Stressor psudopolycythemia • Cigarette smoking • Dehydration : water deprivation, vomiting • Plasma loss : burns.
- 16. Polycythemia Vera Treatment • Todecrease PVC (HCT) – Venesection – Chemotherapy • Treatment of complications
- 17. Essential Thrombocythemia (ET) Primarythrombocytosis / idiopathic thrombocytosis • Clonal myeloproliferative disease of megakaryocytic lineage • Sustained thrombocytosis >450 x 10 9/L & often >1000 x 10 9/L • Increase megakaryocytes in the BM • Thrombotic or/and hemorrhage episodes • 2.5 cases/100,000 • M:F 2:1 • Median age at diagnosis: 60
- 18. Investigations ET is adiagnosis of exclusion • Rule out other causes of elevated platelet count • Infection • Tissue damage (surgery) • Chronic inflammation • Malignancy
- 19. Blood film Bonemarrow increase platelet increase megakaryocyte Essential Thrombocythemia (ET)
- 20. Essential thrombocythemia Primary thrombocytosis/ idiopathic thrombocytosis • Treatment • Anticoagulant for thrombosis • Chemotherapy to decrease platelet count • Disease course and prognosis • 25 % develops myelofibrosis • Acute leukemia transformation • Death due to cardiovascular complication
- 21. Myelofibrosis Chronic idiopathic myelofibrosis •Progressive fibrosis of the marrow & increase connective tissue element • Extramedullary erythropoiesis – Spleen – Liver • Abnormal megakaryocytes which will stimulate fibroblasts &lead to marrow fibrosis due to stimulation of platelet derived growth factor & other protiens secreted by megakayocytes & platelets. • 1/3 of patients have previous history of PV & some present with clinical &lab features of both disorders.
- 22. Myelofibrosis Investigations • Anemia • HighWBC at presentation • Later leucopenia and thrombocytopenia • Leucoerythroblastic blood film • Tear drops red cells • Bone marrow aspiration- Failed due to fibrosis • Trephine biopsy- fibrotic hypercellular marrow • Increase in NAP score • Transformation to acute myeloid leukaemia occurs in 10-20% of patients • High serum uric acid and LDH levels
- 23. Leukoerythroblastic blood pictureTear drop RBCs
- 24. Treatment • Blood transfusionsand regular folic acid • Hydroxyurea • Danazol • Splenectomy • The median survival is 3.5 years • causes of death include heart failure, infection and leukemic transformation.
- 25. Chronic Myeloid Leukemia clonaldisorder that results from a stem cell abnormality marked proliferation of mature and maturing granulocytes. • Most common adult leukemia in Western world • Slight Male predominance
- 26. • The diseaseaccounts for around 15% of leukemia. • Median age at presentation 50 • May occur at any age. • Philadelphia Chromosome t(9;22) is Positive in more than 90% • This translocation is diagnostic of CML
- 27. What is PhiladelphiaChromosome? • Is the chromosome which result from the t(9;22)(q34;q11)part of the Abelson proto-oncogene (ABL) is moved from chromosome 9 to the (BCR) gene on chromosome 22 & part of chromosome 22 moves to chromosome 9. • The abnormal chromosome 22 is the Ph Chromosome code for abnormal tyrosine kinase Tyrosine Kinase leads to persistent proliferation of the white cells Philadelphia Chromosome
- 28. Summary or Conclusion: •MPNs:Clonal hematopoeitic disorders • Proliferation of one or more of myeloid lineages: – Granulocytic – Erythroid – Megakaryocytic • Define chronic Myeloid leukemia • Define Philadelphia chromosome
- 29. Questions? • Define MPN •Mention types of MPNs • What are the diagnostic criteria for PV, ET and MF? • What are the investigations of each type • THANK YOU