Menin-dependent megakaryocyte proliferation and fibrosis in myeloproliferative neoplasms

Résumé fourni par la source

Menin inhibition, an approved therapy for KMT2A -rearranged and NPM1 mutant acute leukemia, is accompanied by decreased platelet counts in 15–20% of heavily pre-treated patients. While studying the mechanism underlying this effect, we discovered that menin inhibition reduced the numbers of megakaryocyte progenitors in human CD34 + cultures and in mice. Because megakaryocytes are key drivers of myeloproliferative neoplasms (MPNs), we investigated the extent to which menin inhibition ameliorates MPN phenotypes. We found that the menin inhibitor revumenib has potent anti-tumor activity, synergizes with ruxolitinib, and shows only subtle effects on healthy mice. Moreover, revumenib suppressed megakaryopoiesis of primary MPN patient specimens in vitro and in vivo . Importantly, genetic knockout of MEN1 and its target MEF2C phenocopied the action of revumenib, confirming an on-target effect of the drug. Together, we reveal menin as a dependency in proliferative megakaryocytes and support further evaluation of menin inhibition as a potential therapy for MPNs.

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