phaidra.vetmeduni.ac.at o:2621 DOI 10.1038/s41467-023-41927-x TET2 lesions enhance the aggressiveness of CEBPA-mutant acute myeloid leukemia by rebalancing GATA2 expression 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. eng Hematopoietic Stem; C/Ebp-Alpha; Mutations Result; Read Alignment; Gene; Evi1; Aml; Transcription; Reveals; Mouse 2024-02-26T11:02:42.419Z LOMv1.0 Author BEGIN:VCARD VERSION:3.0 N:Heyes;Elizabeth; FN:Elizabeth Heyes X-ORCID:https://orcid.org/0000-0003-4306-8251 END:VCARD BEGIN:VCARD VERSION:3.0 N:Porse;Bo T.; FN:Bo T. Porse X-ORCID:https://orcid.org/0000-0001-6043-0844 END:VCARD BEGIN:VCARD VERSION:3.0 N:Grebien;Florian; FN:Florian Grebien X-ORCID:https://orcid.org/0000-0003-4289-2281 END:VCARD BEGIN:VCARD VERSION:3.0 N:Haferlach;Torsten; FN:Torsten Haferlach X-ORCID:https://orcid.org/0000-0003-0196-2837 END:VCARD BEGIN:VCARD VERSION:3.0 N:Schwaller;Jürg; FN:Jürg Schwaller X-ORCID:https://orcid.org/0000-0001-8616-0096 END:VCARD BEGIN:VCARD VERSION:3.0 N:Meggendorfer;Manja; FN:Manja Meggendorfer X-ORCID:https://orcid.org/0000-0002-9038-3265 END:VCARD BEGIN:VCARD VERSION:3.0 N:Schoof;Erwin M.; FN:Erwin M. Schoof X-ORCID:https://orcid.org/0000-0002-3117-7832 END:VCARD BEGIN:VCARD VERSION:3.0 N:Woessmann;Jakob; FN:Jakob Woessmann END:VCARD BEGIN:VCARD VERSION:3.0 N:Gentil;Coline; FN:Coline Gentil END:VCARD BEGIN:VCARD VERSION:3.0 N:Frank;Anne-Katrine; FN:Anne-Katrine Frank X-ORCID:https://orcid.org/0000-0001-6635-6104 END:VCARD BEGIN:VCARD VERSION:3.0 N:D'Altri;Teresa; FN:Teresa D'Altri END:VCARD BEGIN:VCARD VERSION:3.0 N:Pundhir;Sachin; FN:Sachin Pundhir END:VCARD BEGIN:VCARD VERSION:3.0 N:Rzepa;Edwin; FN:Edwin Rzepa END:VCARD BEGIN:VCARD VERSION:3.0 N:Schuster;Mikkel B.; FN:Mikkel B. Schuster END:VCARD BEGIN:VCARD VERSION:3.0 N:Eder;Thomas; FN:Thomas Eder X-ORCID:https://orcid.org/0000-0002-0932-2052 END:VCARD BEGIN:VCARD VERSION:3.0 N:Manhart;Gabriele; FN:Gabriele Manhart END:VCARD BEGIN:VCARD VERSION:3.0 N:Wilhelmson;Anna S.; FN:Anna S. Wilhelmson X-ORCID:https://orcid.org/0000-0003-0640-0251 END:VCARD BEGIN:VCARD VERSION:3.0 N:Wenzel;Anne; FN:Anne Wenzel X-ORCID:https://orcid.org/0000-0001-6187-4156 END:VCARD https://w3id.org/kim/hcrt/scheme https://w3id.org/kim/hcrt/text Textdokument Text LOMv1.0 yes https://creativecommons.org/licenses/by/4.0 application/pdf 8411797 https://phaidra.vetmeduni.ac.at/o:2621 https://phaidra.vetmeduni.ac.at/api/object/o:2621/thumbnail LOMv1.0 discipline