Hmga2 promotes the development of myelofibrosis in Jak2(V617F) knockin mice by enhancing TGF-beta 1 and Cxcl12 pathways

摘要

Myelofibrosis (MF) is a devastating blood disorder. The JAK2V617F mutation has been detected in similar to 50% cases of MF. Elevated expression of high-mobility group AT hook 2 (HMGA2) has also been frequently observed in patients with MF. Interestingly, upregulation of HMGA2 expression has been found in association with the JAK2V617F mutation in significant cases of MF. However, the contribution of HMGA2 in the pathogenesis of MF remains elusive. To determine the effects of concurrent expression of HMGA2 and JAK2V617F mutation in hematopoiesis, we transduced bone marrow cells from Jak2(V617F) knockin mice with lentivirus expressing Hmga2 and performed bone marrow transplantation. Expression of Hmga2 enhanced megakaryopoiesis, increased extramedullary hematopoiesis, and accelerated the development of MF in mice expressing Jak2(V617F). Mechanistically, the data show that expression of Hmga2 enhances the activation of transforming growth factor-beta 1 (TGF-beta 1) and Cxcl12 pathways in mice expressing Jak2(V617F). In addition, expression of Hmga2 causes upregulation of Fzd2, Ifi27l2a, and TGF-beta receptor 2. Forced expression of Cxcl12, Fzd2, or Ifi27l2a increases megakaryocytic differentiation and proliferation in the bone marrow of Jak2(V617F) mice, whereas TGF-beta 1 or Cxcl12 stimulation induces collagen deposition in the bone marrow mesenchymal stromal cells. Together, these findings demonstrate that expression of Hmga2 cooperates with Jak2(V617F) in the pathogenesis of MF.