https://phaidra.vetmeduni.ac.at/o:2621 TET2 lesions enhance the aggressiveness of CEBPA-mutant acute myeloid leukemia by rebalancing GATA2 expression Heyes, Elizabeth Elizabeth Heyes 0000-0003-4306-8251 University of Veterinary Medicine Vienna Porse, Bo T. Bo T. Porse 0000-0001-6043-0844 Copenhagen University Hospital / University of Copenhagen Grebien, Florian Florian Grebien 0000-0003-4289-2281 University of Veterinary Medicine Vienna Haferlach, Torsten Torsten Haferlach 0000-0003-0196-2837 Munich Leukemia Laboratory Schwaller, Jürg Jürg Schwaller 0000-0001-8616-0096 University Children's Hospital Basel Meggendorfer, Manja Manja Meggendorfer 0000-0002-9038-3265 Munich Leukemia Laboratory Schoof, Erwin M. Erwin M. Schoof 0000-0002-3117-7832 Technical University of Denmark Woessmann, Jakob Jakob Woessmann Technical University of Denmark Gentil, Coline Coline Gentil Copenhagen University Hospital / University of Copenhagen Frank, Anne-Katrine Anne-Katrine Frank 0000-0001-6635-6104 Copenhagen University Hospital / University of Copenhagen D'Altri, Teresa Teresa D'Altri Copenhagen University Hospital / University of Copenhagen Pundhir, Sachin Sachin Pundhir Copenhagen University Hospital / University of Copenhagen Rzepa, Edwin Edwin Rzepa University of Veterinary Medicine Vienna Schuster, Mikkel B. Mikkel B. Schuster Copenhagen University Hospital / University of Copenhagen Eder, Thomas Thomas Eder 0000-0002-0932-2052 University of Veterinary Medicine Vienna Manhart, Gabriele Gabriele Manhart University of Veterinary Medicine Vienna Wilhelmson, Anna S. Anna S. Wilhelmson 0000-0003-0640-0251 Copenhagen University Hospital / University of Copenhagen Wenzel, Anne Anne Wenzel 0000-0001-6187-4156 Copenhagen University Hospital / University of Copenhagen Nature Portfolio text eng 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. Hematopoietic Stem; C/Ebp-Alpha; Mutations Result; Read Alignment; Gene; Evi1; Aml; Transcription; Reveals; Mouse http://creativecommons.org/licenses/by/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:2621/download 10.1038/s41467-023-41927-x https://phaidra.vetmeduni.ac.at/o:605 application/pdf Nature Communications 14(1) (2023) Nature Communications 14 1 8.02 MB 2023