| First Author | Ueda K | Year | 2017 |
| Journal | Blood Adv | Volume | 1 |
| Issue | 15 | Pages | 1001-1015 |
| PubMed ID | 29296743 | Mgi Jnum | J:303417 |
| Mgi Id | MGI:6512170 | Doi | 10.1182/bloodadvances.2017004457 |
| Citation | Ueda K, et al. (2017) Hmga2 collaborates with JAK2V617F in the development of myeloproliferative neoplasms. Blood Adv 1(15):1001-1015 |
| abstractText | 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 DeltaHmga2/JAK2(V617F) mice overexpressing Hmga2 due to deletion of the 3' untranslated region. Compared with JAK2(V617F) mice, DeltaHmga2/JAK2(V617F) mice exhibited more severe leukocytosis, anemia and splenomegaly, and shortened survival, whereas severity of myelofibrosis was comparable. DeltaHmga2/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 DeltaHmga2/JAK2(V617F) HSPCs overlapped with those derepressed by Ezh2 loss in JAK2(V617F)/Ezh2(Delta/Delta) HSPCs, suggesting that Hmga2 may facilitate upregulation of Ezh2 targets. Correspondingly, deletion of Hmga2 ameliorated anemia and splenomegaly in JAK2(V617F)/Ezh2(Delta/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. |
