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Status |
Public on Jul 31, 2022 |
Title |
PU.1-dependent enhancer inhibition separates clonal hematopoiesis from malignant transformation (oxBS-Seq) |
Organism |
Mus musculus |
Experiment type |
Methylation profiling by high throughput sequencing
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Summary |
Hematopoietic stem cells sustain life-long blood production. While they are the known cellular origin of aging-associated myeloid malignancies, such as acute myeloid leukemia (AML), mechanisms driving their malignant transformation have remained elusive. Epigenetic dysregulation following acquired loss-of-function mutations of DNA methyl-cytosine dioxygenase Ten-Eleven Translocation-2 (TET2) occurs frequently in the elderly leading to cytosine hypermethylation in and around DNA binding sites of master transcription factors, including PU.1. Here we show that Tet2 deficient hematopoietic stem and progenitor cells (HSPC) undergo malignant transformation upon compromised PU.1 gene regulation. Leukemic stem and progenitor cells show hypermethylation at PU.1 binding sites and fail to activate PU.1-depenent myeloid enhancers, and are hallmarked by a defined signature of impaired genes shared with human AML. Our study demonstrates that Tet2 and PU.1 cooperate in suppressing leukemogenesis in HSPC and establishes a methylation sensitive PU.1-dependent gene network as a unifying feature in acute myeloid leukemia.
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Overall design |
oxidative bisulfite sequencing of cKit+ HSPC purified from UREHETTet2HET and UREHETTet2KO mice and age-matched controls
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Contributor(s) |
Aivalioti MM, Pradhan K, Will B |
Citation(s) |
35820129 |
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Submission date |
Jan 21, 2022 |
Last update date |
Nov 01, 2022 |
Contact name |
Britta Will |
E-mail(s) |
britta.will@einsteinmed.edu
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Organization name |
Albert Einstein College of Medicine
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Department |
Cell Biology
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Street address |
1300 Morris Park Avenue, Chanin Bldg., Rm. #401
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City |
Bronx |
State/province |
NY |
ZIP/Postal code |
10461 |
Country |
USA |
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Platforms (1) |
GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
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Samples (16)
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This SubSeries is part of SuperSeries: |
GSE191053 |
PU.1-dependent enhancer inhibition separates Tet2 deficient clonal hematopoiesis from malignant transformation |
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Relations |
BioProject |
PRJNA799349 |