0423 - Myoproliferative Disorders Flashcards
What is chronic Myeloid leukaemia? What happens if it is left untreated?
A clonal disease that occurs due to an acquired genetic mutation in a pluripotent stem cell. This mutation leads to preferential proliferation of granulocyte progenitors.
Untreated, it goes through a chronic phase, an accelerated phase, and a blast (acute leukaemia) phase.
What is the pathogenesis of CML?
Translocation between chromosomes 9 and 22 produces the Philadelphia Chromosome. This contains a fusion gene - BCR-ABL, which produces a highly-active tyrosine kinase, leading to excessive and dysregulated cell growth.
What are the clinical features of CML?
20-40% diagnosed incidentally.
Otherwise non-specific, fatigue, weight loss, night sweats, splenomegaly, anaemia.
How do you diagnose CML?
Classic changes on peripheral blood (myeloids at all stages of maturation) and bone marrow biopsy (Hypercellularity of myeloid cells at all stages of maturation).
Identification of the BCR-ABL translocation (Philadelphia chromosome)
What are the general treatment aims in chronic myeloproliferative disorders? What is a drug for CML?
Get cell numbers under control (e.g. by phlebotomy, chemo, or bone marrow transplant), and target the specific clone.
Imatinib is a tyrosine kinase inhibitor
What is polycythaemia vera? What causes it?
A chronic myeloproliferative neoplasm characterised by excessive RBC production independent of EPO. Feedback then suppresses EPO.
Caused by a gain-of-function mutation in the JAK-2 gene, allowing phosphorylation and activation of erythropoiesis independent of EPO cytokine.
What are the features of polycythaemia vera?
Increased risk of arterial and venous thromboses.
Microcirculatory disorders - manifest as headaches, visual disturbances, dizziness, erythromelalgia
Hypertension
Plethora (literally excessive blood)
Splenomegaly
How does the JAK-2 mutation work? What diseases is it implicated in?
Allows constitutive tyrosine phosphorylation and activation of downstream pathways independent of cytokine.
Seen in polycythaemia vera, essential thrombocythaemia, primary idiopathic myelofibrosis, and other myeloid disorders.
What is essential thrombocythaemia? What causes it and what does it cause?
Chronic myeloproliferative neoplasm involving megakaryocytes. Leads to thrombocytosis (>450).
Believed caused by JAK2, and causes thrombosis and haemorrhage.
What is Primary myelofibrosis? What causes it and what does it lead to?
Clonal proliferation of megakaryocytes and granulocytes in bone marrow, eventually leads to excessive fibrous connective tissue and extramedullary haematopoiesis.
50% exhibit JAK-2
