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| Status |
Public on Aug 28, 2023 |
| Title |
TET2 lesions enhance the aggressiveness of CEBPA-mutant AML by rebalancing GATA2 expression [RNA-Seq] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
The myeloid transcription factor CEBPA is recurrently biallelically mutated (i.e., double mutated; CEBPADM) in acute myeloid leukemia (AML) with a combination of hypermorphic N-terminal mutations (CEBPANT), promoting expression of the leukemia-associated p30 isoform, and amorphic C-terminal mutations. CEBPADM AML features recurrent co-occurring mutations including GATA2 lesions, however insights into mechanisms governing this co-mutational spectrum are incomplete. By combining transcriptomic and epigenomic analyses of CEBPA-TET2 co-mutated patients with models thereof, we identify GATA2 as a conserved target of the CEBPA-TET2 mutational axis, providing a rationale for the mutational spectra in CEBPADM AML. Mechanistically, we suggest that elevated CEBPA levels, driven by CEBPANT, mediate recruitment of TET2 to the Gata2 distal hematopoietic enhancer thereby increasing Gata2 expression. Conversely, CEBPADM AML gains a competitive advantage through TET2 loss, by decreasing Gata2 promoter demethylation thereby rebalancing GATA2 levels. Of clinical relevance, demethylating treatment of Cebpa-Tet2 co-mutated AML restores Gata2 levels and prolongs disease latency.
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| Overall design |
RNA-seq of Cebpa-/p30 and Cebpa-/p30Tet2-/- AML blasts: Live donor-derived non-lymphoid and non-erythroid bone marrow cells (DAPI-CD45.2+CD3-B220-Ter119-) FACS-sorted. Three biological replicates per genotype were sequenced.
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| Contributor(s) |
Porse BT, Wilhelmson AS, Wenzel A |
| Citation(s) |
37794021 |
| Submission date |
Sep 20, 2022 |
| Last update date |
Oct 18, 2023 |
| Contact name |
Bo Porse |
| Organization name |
University of Copenhagen
|
| Department |
Finsen Laboratory and BRIC
|
| Lab |
Porse lab
|
| Street address |
Ole Maaløes Vej 5, 4
|
| City |
Copenhagen |
| ZIP/Postal code |
2200 |
| Country |
Denmark |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (6)
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| This SubSeries is part of SuperSeries: |
| GSE213864 |
TET2 lesions enhance the aggressiveness of CEBPA-mutant AML by rebalancing GATA2 expression |
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| Relations |
| BioProject |
PRJNA882484 |
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