Titel (eng)

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

Autor*in

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

Verlag

Nature Portfolio

Beschreibung (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.

Sprache des Objekts

Englisch

Datum

2023

Rechte

Dieses Werk bzw. dieser Inhalt steht unter einer
CC BY 4.0 - Creative Commons Namensnennung 4.0 International Lizenz.

CC BY 4.0 International

http://creativecommons.org/licenses/by/4.0/

Klassifikation

Hematopoietic Stem; C/Ebp-Alpha; Mutations Result; Read Alignment; Gene; Evi1; Aml; Transcription; Reveals; Mouse

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