March 1st, 2021: Scientists from the Institute of Medical Biochemistry at Vetmeduni Vienna have already provided important new findings on the development of acute myeloid leukemia (AML), and thus also potential starting points for the treatment of this cancer – which is still associated with a very poor prognosis . In a study that has just been published in “Leukemia”, Elizabeth Heyes and Florian Grebien (Institute for Medical Biochemistry, Vetmeduni Vienna) now identified a protein with MSI2 that could serve as a treatment target for new therapies: If MSI2 is switched off, this delays the onset of the in vivo Leukemia.
Despite recent advances in treatment options, the overall prognosis for most AML patients is poor. Therefore, there is an urgent need for a better understanding of the molecular mechanisms of leukemia development and maintenance in order to develop novel therapies. 10 to 15% of all patients suffering from AML have mutations in the CEBPAGene encoding the transcription factor CCAAT / enhancer binding protein alpha (C / EBPα). Frameshifts in CEBPA-N terminus, which lead to the exclusive expression of a truncated p30 isoform, represent the most common type of CEBPAMutations in AML. C / EBPα p30 interacts with the epigenetic machinery, but it has not yet been clearly understood how p30-induced changes cause leukemia.
MSI2 is vital for AML cancer cells
The scientists at the University of Veterinary Medicine, Vienna hypothesized that critical effector genes are in CEBPAmutated AML depend on a 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. Accompanying p30-dependent changes in gene expression were measured by means of RNA sequencing.
“In an integrative analysis, we were able to determine p30-dependent regulatory elements. The expression of 33 genes was directly controlled by the C / EBPα p30 oncoprotein. A functional study by 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 essential for the survival of murine and human AML cells CEBPA-Mutations required, ”says study lead author Elizabeth Heyes from the Institute for Medical Biochemistry Vetmeduni Vienna.
MSI2 knockdown delays the development of AML in human cells
Now MSI2 has been found in p30-driven murine AML cells and in the CEBPA-mutant human AML cell line KO-52, this caused a proliferation arrest and terminal myeloid differentiation and delayed the onset of leukemia in vivo. In summary, the present study, funded by the European Research Council (ERC) as part of the European Union’s Horizon 2020 research and innovation program, presents a comprehensive data set of p30-dependent effects on epigenetic regulation and gene expression and identifies MSI2 as an effector of C / EBPα p30 -Oncoproteins. Therefore, MSI2 could be a potential new treatment target in patients with CEBPArepresent mutated AML.
to the top
–
