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Heyes, Elizabeth; Wilhelmson, Anna S.; Wenzel, Anne; Manhart, Gabriele; Eder, Thomas; Schuster, Mikkel B.; Rzepa, Edwin; Pundhir, Sachin; D’Altri, Teresa; Frank, Anne-Katrine; Gentil, Coline; Woessmann, Jakob; Schoof, Erwin M.; Meggendorfer, Manja; Schwaller, Jürg; Haferlach, Torsten; Grebien, Florian; Porse, Bo T.
Nature communications, 10/2023, Volume: 14, Issue: 1Journal Article
Abstract 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.
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