Hmga2 collaborates with JAK2V617F in the development of myeloproliferative neoplasms

High-mobility group AT-hook 2 ( HMGA2 ) is crucial for the self-renewal of fetal hematopoietic stem cells (HSCs) but is downregulated in adult HSCs via repression by MIRlet-7 and the polycomb-recessive complex 2 (PRC2) including EZH2. The HMGA2 messenger RNA (mRNA) level is often elevated in patients with myelofibrosis that exhibits an advanced myeloproliferative neoplasm (MPN) subtype, and deletion of Ezh2 promotes the progression of severe myelofibrosis in JAK2 V617F mice with upregulation of several oncogenes such as Hmga2 . However, the direct role of HMGA2 in the pathogenesis of MPNs remains unknown. To clarify the impact of HMGA2 on MPNs carrying the driver mutation, we generated Δ Hmga2 / JAK2 V617F mice overexpressing Hmga2 due to deletion of the 3′ untranslated region. Compared with JAK2 V617F mice, Δ Hmga2 / JAK2 V617F mice exhibited more severe leukocytosis, anemia and splenomegaly, and shortened survival, whereas severity of myelofibrosis was comparable. Δ Hmga2 / JAK2 V617F cells showed a greater repopulating ability that reproduced the severe MPN compared with JAK2 V617F cells in serial bone marrow transplants, indicating that Hmga2 promotes MPN progression at the HSC level. Hmga2 also enhanced apoptosis of JAK2 V617F erythroblasts that may worsen anemia. Relative to JAK2 V617F hematopoietic stem and progenitor cells (HSPCs), over 30% of genes upregulated in Δ Hmga2 / JAK2 V617F HSPCs overlapped with those derepressed by Ezh2 loss in JAK2 V617F / Ezh2 Δ/Δ HSPCs, suggesting that Hmga2 may facilitate upregulation of Ezh2 targets. Correspondingly, deletion of Hmga2 ameliorated anemia and splenomegaly in JAK2 V617F / Ezh2 Δ/wild-type mice, and MIRlet-7 suppression and PRC2 mutations correlated with the elevated HMGA2 mRNA levels in patients with MPNs, especially myelofibrosis. These findings suggest the crucial role of HMGA2 in MPN progression.