Menin-dependent megakaryocyte proliferation and fibrosis in myeloproliferative neoplasms

Menin inhibition, an approved therapy for MLL-rearranged acute myeloid leukemia, is accompanied by decreased platelet counts in 15-20% of heavily pre-treated leukemia patients. While studying the mechanism that accounts for this effect, we discovered that menin inhibition reduced the numbers of megakaryocyte progenitors in human CD34+ cultures and in mice. Given this ability to suppress megakaryopoiesis, which is a key driver of myeloproliferative neoplasms (MPN), we investigated the extent to which menin inhibition ameliorates MPN phenotypes. We found that the menin inhibitor revumenib has potent anti-tumor activity in MPN animal models, leading to significantly increased survival, decreased accumulation of megakaryocytes, normalization of peripheral blood counts, and ablation of bone marrow fibrosis. Revumenib also synergized with the JAK inhibitor ruxolitinib while having subtle effects in healthy mice. Moreover, revumenib suppressed megakaryopoiesis of primary MPN patient specimens in colony forming assays and liquid culture. Importantly, knockout of menin and its target MEIS1 phenocopied the action of revumenib, confirming an on-target effect of the drug. Of note, menin inhibition was not associated with suppression of JAK/STAT signaling indicating that it is a novel dependency. Together we reveal that menin inhibition is a novel therapeutic approach for MPNs.