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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Oct 05, 2023 |
| Title |
HMGA1 Chromatin Regulators Drive MPN Progression [RNA-Seq] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| 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.
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| Overall design |
RNA sequencing (RNAseq) was performed with RNA from of DAMI and SET-2 cell lines with or without HMGA1 silencing.
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| Contributor(s) |
Resar L, Cope L |
| Citation(s) |
35286385 |
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| Submission date |
Sep 03, 2021 |
| Last update date |
Jan 08, 2024 |
| Contact name |
Linda M.S. Resar |
| Organization name |
Johns Hopkins University
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| Department |
Department of Medicine / Division of Hematology
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| Street address |
720 Rutland Avenue
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| City |
BALTIMORE |
| State/province |
Maryland |
| ZIP/Postal code |
21210 |
| Country |
USA |
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| Platforms (1) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
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| Samples (12)
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| This SubSeries is part of SuperSeries: |
| GSE189570 |
HMGA1 Chromatin Regulators Drive MPN Progression |
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| Relations |
| BioProject |
PRJNA760443 |
| SRA |
SRP335549 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE183374_RAW.tar |
52.3 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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