02.11.2023: A European research team led by the University of Veterinary Medicine Vienna has discovered a new puzzle piece for understanding how acute myeloid leukaemia (AML) develops. The findings could help to develop specific therapies to target CEBPA-mutated AML which affects up to 15% of all newly diagnosed AML patients.
Acute myeloid leukaemia (AML) is characterised by genetic changes that impair the proliferation and/or differentiation of haematopoietic stem or progenitor cells. If left untreated, this ultimately leads to bone marrow failure and death. Recent sequencing studies have identified numerous disease-causing mutations in AML and have revealed patterns of co-occurring mutations. The exact basis for these mutations, however, remains largely unexplained.
First explanation of certain mutation patterns in CEBPA-mutated AML
One of these unsolved mysteries in AML disease development concerns CCAAT enhancer binding protein alpha (CEBPA), a transcription factor that is required for the differentiation and maturation of granulocytes, an important group of white blood cells. The gene that codes for CEBPA is mutated in 3–15% of newly diagnosed AML patients. The most commonly co-mutated genes in CEBPA-mutated AML are GATA2 and TET2 – but the molecular mechanisms underlying this spectrum of specific co-mutations remain elusive.
A European research team led by Vetmeduni, in collaboration with the University of Copenhagen, has now been able to describe the mechanism responsible for this for the first time. “By combining transcriptomic and epigenomic analyses of patients with CEBPA-TET2 co-mutations, we identified GATA2 as the target of the CEBPA-TET2 mutational axis, which provides an explanation for the mutational spectra in CEBPA-mutated AML,” says study co-first author Elizabeth Heyes from Vetmeduni’s Institute of Medical Biochemistry.
New research findings could enable targeted therapies
The research findings suggest a specific molecular mechanism. “We propose an intricate mechanism by which increased levels of a certain AML-specific mutated CEBPA isoform mediates binding of TET2 to regulatory regions of the GATA2 gene to promote its expression,” explains study co-last author Florian Grebien, head of the Institute of Medical Biochemistry at Vetmeduni. “We show that elevated GATA2 levels are disadvantageous for CEBPA-mutated leukaemia cells and that this can be counteracted by the loss of TET2. This mechanism provides an explanation for the co-occurrence of CEBPA and TET2 lesions in AML. Finally, the repression of GATA2 expression caused by TET2 deficiency can be counteracted by treatment with 5-azacytidine, which is a clinically available drug”. According to the researchers, this provides an entry point for the development of targeted therapies in AML patients with these mutations.
The article “TET2 lesions enhance the aggressiveness of CEBPA-mutant acute myeloid leukemia by rebalancing GATA2 expression” by Elizabeth Heyes, Anna S. Wilhelmson, Anne Wenzel, Gabriele Manhart, Thomas Eder, Mikkel B. Schuster, Edwin Rzepa, Sachin Pundhir, Teresa D’Altri, Anne-Katrine Frank, Coline Gentil, Jakob Woessmann, Erwin M. Schoof, Manja Meggendorfer, Jürg Schwaller, Torsten Haferlach, Florian Grebien and Bo T. Porse was published in Nature Communications.