Mutant ASXL1 exacerbates CALR-mutant myeloproliferative neoplasms by enhancing a distinct megakaryocyte differentiation program.

Calr-Asxl1 co-mutant mice develop more severe thrombocytosis and splenomegaly than Calr single-mutant mice, linked to a stronger megakaryocyte differentiation program.

• Why it matters: ASXL1 mutations worsen outcomes in myeloid neoplasms, but how they intensify CALR-mutant MPN biology—especially via megakaryocytes—remains unclear.
• What they did: The study generated Calr-Asxl1 co-mutant mice, assessed megakaryocyte morphology and emperipolesis, mapped a megakaryocyte-biased HSC-to-megakaryocyte trajectory, and tested human relevance using GoT on primary MPN bone marrow.
• The result: The non-canonical trajectory was more prominent and showed Mef2c upregulation, with mature co-mutant megakaryocytes in a proinflammatory state and HSCs showing inflammation-resistance, confirmed in human CALR-ASXL1 co-mutant samples.

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