TET2 lesions enhance the aggressiveness of CEBPA-mutant acute myeloid leukemia by rebalancing GATA2 expression

Elizabeth Heyes, Anna S. Wilhelmson, Anne Wenzel, Gabriele Manhart, Thomas Eder, Mikkel B. Schuster, Edwin Rzepa, Sachin Pundhir, Teresa D’Altri, Anne-Katrine Frank, Coline Gentil, Jakob Woessmann, Erwin M. Schoof, Manja Meggendorfer, Jürg Schwaller, Torsten Haferlach, Florian Grebien () and Bo T. Porse ()
Additional contact information
Elizabeth Heyes: University of Veterinary Medicine, Institute of Medical Biochemistry
Anna S. Wilhelmson: Copenhagen University Hospital - Rigshospitalet
Anne Wenzel: Copenhagen University Hospital - Rigshospitalet
Gabriele Manhart: University of Veterinary Medicine, Institute of Medical Biochemistry
Thomas Eder: University of Veterinary Medicine, Institute of Medical Biochemistry
Mikkel B. Schuster: Copenhagen University Hospital - Rigshospitalet
Edwin Rzepa: University of Veterinary Medicine, Institute of Medical Biochemistry
Sachin Pundhir: Copenhagen University Hospital - Rigshospitalet
Teresa D’Altri: Copenhagen University Hospital - Rigshospitalet
Anne-Katrine Frank: Copenhagen University Hospital - Rigshospitalet
Coline Gentil: Copenhagen University Hospital - Rigshospitalet
Jakob Woessmann: Technical University of Denmark
Erwin M. Schoof: Technical University of Denmark
Manja Meggendorfer: MLL Munich Leukemia Laboratory
Jürg Schwaller: University Children’s Hospital Basel
Torsten Haferlach: MLL Munich Leukemia Laboratory
Florian Grebien: University of Veterinary Medicine, Institute of Medical Biochemistry
Bo T. Porse: Copenhagen University Hospital - Rigshospitalet

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract 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. The most frequently co-mutated genes in CEBPADM 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 CEBPADM AML. Elevated CEBPA levels, driven by CEBPANT, mediate recruitment of TET2 to the Gata2 distal hematopoietic enhancer thereby increasing Gata2 expression. Concurrent loss of TET2 in CEBPADM 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.

Date: 2023
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DOI: 10.1038/s41467-023-41927-x

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