Gata2 promotes drug resistance in Acute Myeloid Leukemia (AML) [ChIP-Seq]
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ABSTRACT:
PROVIDER: PRJNA1103845 | ENA |
REPOSITORIES: ENA
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Project description:Gata2 promotes drug resistance in Acute Myeloid Leukemia (AML)
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Project description:GATA2 is a transcription factor essential for hematopoietic differentiation and lymphatic system formation. High expression of GATA2 has been implicated in myelodysplastic syndrome and acute myeloid leukemia. Bortezomib has a good effect in MM. However, the mechanism of bortezomib possesses anti-self-renewal and leukemogenesis in AML is still unclear. Here, we reported that GATA2 and WT1 protein is degraded by bortezomib. The half-life of GATA2 mRNA was obviously shorter in Bortezomib-treated cells. Knockdown of GATA2 by small hairpin RNAs (shRNAs) has potential anti-leukemia activity in leukemic cells. Bortezomib inhibited cell proliferation and induced apoptotic death without activation of caspases pathway. Finally, bortezomib decreased xenograft tumor size in a xenograft leukemia mouse model, and prolonged the survival time in mouse C1498 AML model. Collectively, bortezomib might be a potential treatment for AML.
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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.
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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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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.
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