Calreticulin (CALR) exon 9 mutations are found in approximately 25% of essential thrombocythaemia and myelofibrosis patients. How do CALR mutations drive myeloproliferation?

• A Direct activation of JAK2 V617F-independent JAK-STAT pathway via MPL ✓
• B Loss-of-function causing accumulation of misfolded proteins
• C Aberrant calreticulin acts as a lectin chaperone for EPO receptor
• D CALR mutation activates BCR-ABL fusion protein

Explanation

CALR frameshift mutations result in a novel C-terminal domain that aberrantly binds to and constitutively activates the thrombopoietin receptor (MPL/c-MPL), leading to JAK2-STAT5 pathway activation independent of the JAK2 V617F mutation. This explains the myeloproliferative phenotype (thrombocytosis, megakaryocyte proliferation) without JAK2 V617F. CALR-mutated MPN generally has better prognosis than JAK2-mutated disease. The mutant CALR protein forms a complex with MPL in the ER.

Reference: Harrison's Principles of Internal Medicine, 21st ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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