o:2621 TET2 lesions enhance the aggressiveness of CEBPA-mutant acute myeloid leukemia by rebalancing GATA2 expression en 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 1552099 10.1038/s41467-023-41927-x 2024-02-26T10:56:38.551Z 44 yes 46 Elizabeth Heyes University of Veterinary Medicine Vienna 0000-0003-4306-8251 Anna S. Wilhelmson Copenhagen University Hospital / University of Copenhagen person 0000-0003-0640-0251 Anne Wenzel Copenhagen University Hospital / University of Copenhagen person 0000-0001-6187-4156 Gabriele Manhart University of Veterinary Medicine Vienna person Thomas Eder University of Veterinary Medicine Vienna person 0000-0002-0932-2052 Mikkel B. Schuster Copenhagen University Hospital / University of Copenhagen person Edwin Rzepa University of Veterinary Medicine Vienna person Sachin Pundhir Copenhagen University Hospital / University of Copenhagen person Teresa D'Altri Copenhagen University Hospital / University of Copenhagen person Anne-Katrine Frank Copenhagen University Hospital / University of Copenhagen person 0000-0001-6635-6104 Coline Gentil Copenhagen University Hospital / University of Copenhagen person Jakob Woessmann Technical University of Denmark person Erwin M. Schoof Technical University of Denmark person 0000-0002-3117-7832 Manja Meggendorfer Munich Leukemia Laboratory person 0000-0002-9038-3265 Jürg Schwaller University Children's Hospital Basel person 0000-0001-8616-0096 Torsten Haferlach Munich Leukemia Laboratory person 0000-0003-0196-2837 Florian Grebien University of Veterinary Medicine Vienna person 0000-0003-4289-2281 Bo T. Porse Copenhagen University Hospital / University of Copenhagen person 0000-0001-6043-0844 application/pdf 8411797 https://phaidra.vetmeduni.ac.at/o:2621 no yes 16 70 1552253 Nature Communications 18 14 1 Nature Portfolio 2023