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Series GSE189568 Query DataSets for GSE189568
Status Public on Oct 05, 2023
Title HMGA1 Chromatin Regulators Drive MPN Progression [ATAC-Seq]
Organism Homo sapiens
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Summary Myeloproliferative neoplasms (MPN) transform to myelofibrosis (MF) and highly lethal acute myeloid leukemia (AML), although actionable mechanisms driving progression remain elusive. The HMGA1 chromatin regulator is up-regulated during MPN progression with highest levels after transformation. HMGA1 depletion in JAK2V617F MPN AML cell lines disrupts proliferation, clonogenicity, and leukemic engraftment. Surprisingly, loss of just a single Hmga1 allele prevents progression to MF in JAK2V617F transgenic mice, decreasing blood counts and expansion in stem and myeloid progenitors while preventing splenomegaly and fibrosis within the spleen and bone marrow. RNA sequencing revealed HMGA1-dependent transcriptional networks that govern proliferation (E2F, G2M, mitosis, MYC targets) and cell fate, including the GATA2 master regulatory gene. Silencing GATA2 recapitulates 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 GATA2, are activated in human MF after leukemic transformation. Further, HMGA1 depletion synergizes with the JAK2 inhibitor, ruxolitinib, to prolong survival in murine MPN AML. These findings illuminate HMGA1 as a key epigenetic switch required for MPN transformation and promising therapeutic target to treat or prevent disease progression.
 
Overall design ATAC sequencing (ATACseq) was performed with RNA from of DAMI and SET-2 cell lines with or without HMGA1 silencing.
 
Contributor(s) Resar L, Cope L
Citation(s) 35286385
Submission date Nov 25, 2021
Last update date Jan 08, 2024
Contact name Linda M.S. Resar
Organization name Johns Hopkins University
Department Department of Medicine / Division of Hematology
Street address 720 Rutland Avenue
City BALTIMORE
State/province Maryland
ZIP/Postal code 21210
Country USA
 
Platforms (1)
GPL16791 Illumina HiSeq 2500 (Homo sapiens)
Samples (6)
GSM5704006 DAMI TRC rep 1
GSM5704007 DAMI TRC rep 2
GSM5704008 DAMI TRC rep 3
This SubSeries is part of SuperSeries:
GSE189570 HMGA1 Chromatin Regulators Drive MPN Progression
Relations
BioProject PRJNA783622

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Supplementary file Size Download File type/resource
GSE189568_Con_hg19_genrich_sorted.narrowPeak.gz 3.1 Mb (ftp)(http) NARROWPEAK
GSE189568_shHMGA1_hg19_genrich_sorted.narrowPeak.gz 2.7 Mb (ftp)(http) NARROWPEAK
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Raw data are available in SRA
Processed data are available on Series record

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