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MSI2 – New factor discovered for the development of leukaemia with specific mutations

01.03.2021: Researchers from the Institute for Medical Biochemistry at Vetmeduni have already made important new discoveries into the development of acute myeloid leukaemia (AML) in the past, providing potential strategies for the treatment of this cancer form, which continues to have a very poor prognosis even today. In a recent study published in Leukemia, Elizabeth Heyes and Florian Grebien from the Institute for Medical Biochemistry identified the protein MSI2 as a potential target for new therapies. Their study shows that switching off MSI2 delays the onset of leukaemia in vivo.

Despite recent advances in therapeutic options, the overall prognosis for most AML patients remains poor. Therefore, there is an urgent need to better understand the molecular mechanisms of leukaemia development and maintenance in order to develop novel therapeutic approaches. Between 10 % and 15 % of AML patients exhibit mutations in the CEBPA gene that encodes the transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα). Frameshifts in the CEBPA N-terminus resulting in the exclusive expression of a truncated p30 isoform represent the most common type of CEBPA mutations in AML. C/EBPα p30 interacts with the epigenetic machinery, but the exact mechanism how p30-mediated changes cause leukaemia remains incompletely understood.

MSI2 essential for survival of AML cancer cells

The researchers from the University of Veterinary Medicine Vienna hypothesized that critical effector genes in CEBPA-mutated AML depend on p30-mediated dysregulation of the epigenome. To test their hypothesis, they mapped p30-associated regulatory elements in a myeloid progenitor cell model for p30-driven AML. Concomitant p30-dependent changes in gene expression were measured through RNA sequencing.

“Applying an integrative analysis, we were able to identify p30-dependent regulatory elements. The expression of 33 genes was directly regulated by the C/EBPα p30 oncoprotein. A functional investigation using CRISPR/Cas9 screening identified the RNA-binding protein MUSASHI-2 (MSI2) as a critical effector of p30. AML patients with CEBPA mutations expressed high levels of MSI2, and MSI2 was required for survival of murine and human AML cells with CEBPA mutations,” says first author Elizabeth Heyes from the Institute for Medical Biochemistry at Vetmeduni.

MSI2 knockout delays the development of AML in human cells

Switching off MSI2 in p30-driven murine AML cells and in the CEBPA-mutated human AML cell line KO-52 caused proliferation arrest and terminal myeloid differentiation and delayed leukaemia onset in vivo. In summary, the present study, which was financed by the European Research Council (ERC) as part of the EU’s Horizon 2020 funding programme for research and innovation, provides a comprehensive dataset of p30-dependent effects on epigenetic regulation and gene expression and identifies MSI2 as an effector of the C/EBPα p30 oncoprotein. The study therefore establishes MSI2 as a potential new target in patients with CEBPA-mutated AML.

The article “Identification of gene targets of mutant C/EBPα reveals a critical role for MSI2 in CEBPA-mutated AML” by Elizabeth Heyes, Luisa Schmidt, Gabriele Manhart, Thomas Eder, Ludovica Proietti and Florian Grebien was published Leukemia.