Classical myeloproliferative neoplasms (MPNs), consisting of polycythemia vera, essential thrombocythemia and primary myelofibrosis (PMF), are chronic blood cancers characterized by the overproduction of mature blood cells. Classical MPNs are BCR–ABL1-negative, distinguishing them from chronic myeloid leukaemia, and are instead driven by mutations in JAK2, MPL or CALR that result in constitutive activation of the JAK–STAT pathway. The classical MPNs share abnormalities of the megakaryocyte lineage that drive pathogenesis, directly contributing to both bone marrow fibrosis and peripheral thrombocytosis. Whereas JAK inhibitors such as ruxolitinib effectively reduce symptom burden, they exhibit limited effects on bone marrow fibrosis, and responses are frequently not durable. Clinical observations that menin inhibitors, including revumenib, induce thrombocytopenia as a common adverse event in patients with acute leukaemia, together with emerging evidence that targeting the megakaryocyte lineage could provide therapeutic benefit in MPNs, prompted Wen, Cotton et al. to investigate the effects of menin inhibition on the megakaryocyte lineage and explore its therapeutic potential in MPNs.
Single-cell RNA sequencing of cultured CD34+ cells following menin inhibition with revumenib or genetic deletion of MEN1 revealed a reduction in both MKPs and mature megakaryocytes compared with controls. This was accompanied by reduced expression of canonical menin–KMT2A target genes, including MEIS1, MEF2C and PBX3 in MKPs and MEF2C and PBX3 in mature megakaryocytes.
