TET2 lesions enhance the aggressiveness of CEBPA-mutant acute myeloid leukemia by rebalancing GATA2 expression
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The myeloid transcription factor CEBPA is recurrently biallelically mutated (i.e., double mutated; CEBPA DM) in acute myeloid leukemia (AML) with a combination of hypermorphic N-terminal mutations (CEBPA NT), promoting expression of the leukemia-associated p30 isoform, and amorphic C-terminal mutations. The most frequently co-mutated genes in CEBPA DM AML are GATA2 and TET2, however the molecular mechanisms underlying 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 CEBPA DM AML. Elevated CEBPA levels, driven by CEBPA NT, mediate recruitment of TET2 to the Gata2 distal hematopoietic enhancer thereby increasing Gata2 expression. Concurrent loss of TET2 in CEBPA DM AML induces a competitive advantage by increasing Gata2 promoter methylation, thereby rebalancing GATA2 levels. Of clinical relevance, demethylating treatment of Cebpa-Tet2 co-mutated AML restores Gata2 levels and prolongs disease latency.
| Original language | English |
|---|---|
| Article number | 6185 |
| Journal | Nature Communications |
| Volume | 14 |
| Number of pages | 18 |
| ISSN | 2041-1723 |
| DOIs | |
| Publication status | Published - 2023 |
Bibliographical note
Funding Information:
Work in the Porse lab was supported by grants from the Copenhagen University Hospital, the Capital Region of Copenhagen, the Independent Research Fund Denmark (9039-00189B) and through a center grant from the Novo Nordisk Foundation (Novo Nordisk Foundation Center for Stem Cell Biology, DanStem; Grant Number NNF17CC0027852). This work has been performed in the context of the Danish Research Center for Precision Medicine in Blood Cancers funded by the Danish Cancer Society (R223-A13071) and Greater Copenhagen Health Science Partners. Work in the Grebien lab was supported by the European Union’s Horizon 2020 research and innovation program (European Research Council grant agreement No 636855 and Austrian Science Fund (FWF), grants no. TAI-490 and P35628. Work in the Schoof lab was supported by a grant from the Independent Research Fund Denmark (case no. 2067-00053B). ASW was supported by grants from The Lundbeck Foundation (R303-2018-2868) and The Swedish Research Council (2015-00517). EH was supported by a grant from Forschungsförderung from the Fellinger Krebsforschungsverein. We thank members of the Grebien and Porse laboratories for their discussions. We thank Anna Fossum for her excellent research assistance.
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© 2023, Springer Nature Limited.
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