ABSTRACT
Myeloproliferative neoplasms (MPNs) transform to myelofibrosis (MF) and highly lethal acute myeloid leukemia (AML), although the actionable mechanisms driving progression remain elusive. Here, we elucidate the role of the high mobility group A1 (HMGA1) chromatin regulator as a novel driver of MPN progression. HMGA1 is upregulated in MPN, with highest levels after transformation to MF or AML. To define HMGA1 function, we disrupted gene expression via CRISPR/Cas9, short hairpin RNA, or genetic deletion in MPN models. HMGA1 depletion in JAK2V617F AML cell lines disrupts proliferation, clonogenicity, and leukemic engraftment. Surprisingly, loss of just a single Hmga1 allele prevents progression to MF in JAK2V617F mice, decreasing erythrocytosis, thrombocytosis, megakaryocyte hyperplasia, and expansion of stem and progenitors, while preventing splenomegaly and fibrosis within the spleen and BM. RNA-sequencing and chromatin immunoprecipitation sequencing revealed HMGA1 transcriptional networks and chromatin occupancy at genes that govern proliferation (E2F, G2M, mitotic spindle) and cell fate, including the GATA2 master regulatory gene. Silencing GATA2 recapitulates most phenotypes observed with HMGA1 depletion, whereas GATA2 re-expression partially rescues leukemogenesis. HMGA1 transactivates GATA2 through sequences near the developmental enhancer (+9.5), increasing chromatin accessibility and recruiting active histone marks. Further, HMGA1 transcriptional networks, including proliferation pathways and GATA2, are activated in human MF and MPN leukemic transformation. Importantly, HMGA1 depletion enhances responses to the JAK2 inhibitor, ruxolitinib, preventing MF and prolonging survival in murine models of JAK2V617F AML. These findings illuminate HMGA1 as a key epigenetic switch involved in MPN transformation and a promising therapeutic target to treat or prevent disease progression.
Subject(s)
GATA2 Transcription Factor , HMGA1a Protein , Leukemia, Myeloid, Acute , Myeloproliferative Disorders , Primary Myelofibrosis , Animals , Cell Proliferation , Chromatin/genetics , GATA2 Transcription Factor/genetics , Gene Regulatory Networks , HMGA1a Protein/genetics , HMGA1a Protein/metabolism , Janus Kinase 2/genetics , Janus Kinase 2/metabolism , Leukemia, Myeloid, Acute/genetics , Mice , Myeloproliferative Disorders/genetics , Myeloproliferative Disorders/metabolism , Primary Myelofibrosis/geneticsABSTRACT
Arcobacter spp. are commonly associated with shellfish and have been increasingly implicated in human gastrointestinal disease. We report the first case of human bacteremia with Malacobacter (previously Arcobacter) mytili acquired after exposure to Maryland crab. Arcobacter spp. should be considered in febrile illnesses when the history indicates exposure to seafood.
