한빛사 논문
Liping Li 1, Jung-Hyun Kim 1, Wenyan Lu 1, Donna M Williams 1, Joseph Kim 1, Leslie Cope 2, Raajit K Rampal 3, Richard P Koche 3, Lingling Xian 1, Li Z Luo 1, Marija Vasiljevic 1, Daniel R Matson 4, Zhizhuang Joe Zhao 5, Ophelia Rogers 1, Matthew C Stubbs 6, Karen Reddy 7, Antonio-Rodriguez Romero 8, Bethan Psaila 8, Jerry L Spivak 1 2, Alison R Moliterno 1, Linda M S Resar 1 2 9 10
1Division of Hematology, Department of Medicine, and.
2Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD.
3Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Center for Epigenetics Research, Memorial Sloan Kettering Cancer Institute, New York, NY.
4Blood Cancer Research Institute, Department of Cell and Regenerative Biology, UW Carbone Cancer Center, University of Wisconsin School of Medicine, Madison, WI.
5Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
6Pharmacology, Incyte Research Institute, Wilmington, DE.
7Department of Biologic Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD.
8MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine and National Institutes of Health Research (NIHR) Oxford Biomedical Research Centre, University of Oxford, Oxford, UK; and.
9Cellular and Molecular Medicine Graduate Program and.
10Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD.
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.
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