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TET2 lesions enhance the aggressiveness of CEBPA-mutant AML by rebalancing GATA2 expression

ABSTRACT: TET2 lesions enhance the aggressiveness of CEBPA-mutant AML by rebalancing GATA2 expression

PROVIDER: PRJNA882806 | ENA |

REPOSITORIES: ENA

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TET2 lesions enhance the aggressiveness of CEBPA-mutant AML by rebalancing GATA2 expression [WGBS]

Project description: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.

2023-08-28 | GSE213860 | GEO

TET2 lesions enhance the aggressiveness of CEBPA-mutant AML by rebalancing GATA2 expression [RNA-Seq]

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TET2 lesions enhance the aggressiveness of CEBPA-mutant AML by rebalancing GATA2 expression [WGBS]

Project description:TET2 lesions enhance the aggressiveness of CEBPA-mutant AML by rebalancing GATA2 expression [WGBS]

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TET2 lesions enhance the aggressiveness of CEBPA-mutant AML by rebalancing GATA2 expression [RNA-Seq]

Project description:TET2 lesions enhance the aggressiveness of CEBPA-mutant AML by rebalancing GATA2 expression [RNA-Seq]

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TET2 lesions enhance the aggressiveness of CEBPA-mutant AML by re-balancing GATA2 expression

Project description: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; however, insight into the underlying mechanisms for the co-mutational spectra is incomplete. By combining transcriptomic and epigenomic analyses of data from CEBPA-TET2-co-mutant patients with experimental 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 the CEBPANT, mediate recruitment of TET2 to the GATA2 distal hematopoietic enhancer and thereby increase GATA2 expression. Conversely, CEBPADM AML gains a competitive advantage by loss of TET2; decreasing GATA2 promoter demethylation and re-balancing GATA2 levels. Further, demethylating treatment of CEBPA-TET2-co-mutant AML restores GATA2 levels, and prolongs disease latency.

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TET2 lesions enhance the aggressiveness of CEBPA-mutant AML by re-balancing GATA2 expression

Project description:TET2 lesions enhance the aggressiveness of CEBPA-mutant AML by re-balancing GATA2 expression

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TET2 lesions enhance the aggressiveness of CEBPA-mutant AML by rebalancing GATA2 expression

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-08-28 | GSE213864 | GEO

Allele-specific expression of GATA2 due to epigenetic dysregulation in double mutated CEBPA AML

Project description:Transcriptional deregulation is a central event in the development of acute myeloid leukemia (AML). To identify potential disturbances in gene regulation, we conducted an unbiased screen of allele-specific expression (ASE) in 209 AML cases. The gene encoding GATA binding protein 2 (GATA2) displayed ASE more often than any other myeloid or cancer-related gene. GATA2 ASE was strongly associated with CEBPA double mutations (CEBPA DM), with 95% of cases presenting GATA2 ASE. In CEBPA DM AML with GATA2 mutations, the mutated allele was preferentially expressed. We found that GATA2 ASE is a somatic event lost in complete remission, supporting the notion that it plays a role in CEBPA DM AML. Acquisition of GATA2 ASE involved silencing of one allele via promoter methylation, compensated by overactivation of the other allele, thereby preserving expression levels. Notably, promoter methylation was also lost in remission together with GATA2 ASE. In summary, we propose that GATA2 ASE is acquired by epigenetic mechanisms and is a prerequisite for the development of AML with CEBPA DM. This finding constitutes a novel example of an epigenetic hit cooperating with a genetic hit in the pathogenesis of AML.

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