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

• Published in: Nature communications Vol. 14; no. 1; p. 6185
• Main Authors: Heyes, Elizabeth, Wilhelmson, Anna S., Wenzel, Anne, Manhart, Gabriele, Eder, Thomas, Schuster, Mikkel B., Rzepa, Edwin, Pundhir, Sachin, D’Altri, Teresa, Frank, Anne-Katrine, Gentil, Coline, Woessmann, Jakob, Schoof, Erwin M., Meggendorfer, Manja, Schwaller, Jürg, Haferlach, Torsten, Grebien, Florian, Porse, Bo T.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.10.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/31; 13/44; 13/89; 14/35; 38/15; 38/23; 38/39; 38/77; 631/208/176/1988; 631/67/1990/283/1897; 64/60; 692/699/1541/1990/283/1897; Acute myeloid leukemia; DNA methylation; Genes; Humanities and Social Sciences; Latency; Leukemia; Molecular modelling; multidisciplinary; Mutation; Science; Science (multidisciplinary); Transcriptomics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-41927-x

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. TET2 and GATA2 are two frequently co-mutated genes in CEBPA double mutated acute myeloid leukemia (AML). Here the authors show that the underlying mechanism for this cooccurrence is for TET2 loss-of-function mutation to counteract the increase in GATA2 expression, which is disadvantageous to these type of AML cells.