Title (en)
TET2 lesions enhance the aggressiveness of CEBPA-mutant acute myeloid leukemia by rebalancing GATA2 expression
Language
English
Description (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.
Keywords (en)
Hematopoietic Stem; C/Ebp-Alpha; Mutations Result; Read Alignment; Gene; Evi1; Aml; Transcription; Reveals; Mouse
DOI
10.1038/s41467-023-41927-x
Author of the digital object
Elizabeth Heyes  (University of Veterinary Medicine Vienna)
Bo T. Porse  (Copenhagen University Hospital / University of Copenhagen)
Florian Grebien  (University of Veterinary Medicine Vienna)
Torsten Haferlach  (Munich Leukemia Laboratory)
Jürg Schwaller  (University Children's Hospital Basel)
Manja Meggendorfer  (Munich Leukemia Laboratory)
Erwin M. Schoof  (Technical University of Denmark)
Jakob Woessmann  (Technical University of Denmark)
Coline Gentil  (Copenhagen University Hospital / University of Copenhagen)
Anne-Katrine Frank  (Copenhagen University Hospital / University of Copenhagen)
Teresa D'Altri  (Copenhagen University Hospital / University of Copenhagen)
Sachin Pundhir  (Copenhagen University Hospital / University of Copenhagen)
Edwin Rzepa  (University of Veterinary Medicine Vienna)
Mikkel B. Schuster  (Copenhagen University Hospital / University of Copenhagen)
Thomas Eder  (University of Veterinary Medicine Vienna)
Gabriele Manhart  (University of Veterinary Medicine Vienna)
Anna S. Wilhelmson  (Copenhagen University Hospital / University of Copenhagen)
Anne Wenzel  (Copenhagen University Hospital / University of Copenhagen)
Format
application/pdf
Size
8.0 MB
Licence Selected
CC BY 4.0 International
Type of publication
Article
Name of Publication (en)
Nature Communications
Pages or Volume
18
Volume
14
Number
1
Publisher
Nature Portfolio
Publication Date
2023