Myeloproliferative neoplasms (MPNs) advance to myelofibrosis (MF) and fatal acute myeloid leukemia (AML), but the actionable mechanisms underlying progression were unknown. For a study, researchers investigated the involvement of the chromatin regulator high mobility group A1 (HMGA1) is a new driver of MPN development. HMGA1 was increased in MPN, peaking following the transition to MF or AML. In MPN models, they altered gene expression using CRISPR/Cas9, short hairpin RNA, or genetic deletion to determine HMGA1 function. In JAK2V617F AML cell lines, HMGA1 depletion inhibits proliferation, clonogenicity, and leukemic engraftment. Surprisingly, deletion of a single Hmga1 allele inhibits progression to MF in JAK2V617F animals, lowering erythrocytosis, thrombocytosis, megakaryocyte hyperplasia, and stem and progenitor expansion, while avoiding splenomegaly and BM fibrosis. RNA-sequencing and chromatin immunoprecipitation sequencing revealed HMGA1 transcriptional networks and chromatin occupancy at genes that control proliferation (E2F, G2M, mitotic spindle) and cell fate, including the master regulating gene GATA2. Most abnormalities seen with HMGA1 depletion are recapitulated by silencing GATA2, although GATA2 re-expression partly restores leukemogenesis. GATA2 is transactivated by HMGA1 through regions near the developmental enhancer (+9.5), enhancing chromatin accessibility and attracting active histone marks. Furthermore, human MF and MPN leukemic transition activate HMGA1 transcriptional networks, including proliferative pathways and GATA2. Importantly, in mouse models of JAK2V617F AML, HMGA1 reduction improves responses to the JAK2 drug ruxolitinib, avoiding MF and extending life. The findings highlighted HMGA1 as a critical epigenetic switch in MPN transformation and a possible therapeutic target for treating or preventing disease development.
