TET2 lesions enhance the aggressiveness of CEBPA-mutant acute myeloid leukemia by rebalancing GATA2 expression.
Elizabeth HeyesAnna S WilhelmsonAnne WenzelGabriele ManhartThomas EderMikkel B SchusterEdwin RzepaSachin PundhirTeresa D'AltriAnne-Katrine FrankColine GentilJakob WoessmannErwin M SchoofManja MeggendorferJuerg SchwallerTorsten HaferlachFlorian GrebienBo Torben PorsePublished in: Nature communications (2023)
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.
Keyphrases
- transcription factor
- acute myeloid leukemia
- allogeneic hematopoietic stem cell transplantation
- dna binding
- poor prognosis
- genome wide identification
- bone marrow
- type diabetes
- adipose tissue
- binding protein
- clinical trial
- gene expression
- squamous cell carcinoma
- dendritic cells
- acute lymphoblastic leukemia
- minimally invasive
- insulin resistance
- glycemic control
- single cell