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Methylation and silencing of miRNA-124 by EVI1 and self-renewal exhaustion of hematopoietic stem cells in murine myelodysplastic syndrome. | LitMetric

AI Article Synopsis

  • Researchers developed a myelodysplastic syndrome (MDS) model in mice by expressing a gene called EVI1, leading to severe blood issues and eventual death after 11-14 months post-bone marrow transplantation.
  • A specific mutant version of EVI1 (EVI1-(1+6Mut)), which cannot bind to another protein (Gata1), prevented the onset of MDS, restoring normal blood cell production and bone marrow function for up to 21 months.
  • The study found that EVI1 disrupts gene regulation related to cell division and self-renewal, primarily through altering miRNA expression, with significant differences in activity between the EVI1 and its mutant form.

Article Abstract

By expressing EVI1 in murine bone marrow (BM), we previously described a myelodysplastic syndrome (MDS) model characterized by pancytopenia, dysmegakaryopoiesis, dyserythropoiesis, and BM failure. The mice invariably died 11-14 months after BM transplantation (BMT). Here, we show that a double point mutant EVI1-(1+6Mut), unable to bind Gata1, abrogates the onset of MDS in the mouse and re-establishes normal megakaryopoiesis, erythropoiesis, BM function, and peripheral blood profiles. These normal features were maintained in the reconstituted mice until the study was ended at 21 months after BMT. We also report that EVI1 deregulates several genes that control cell division and cell self-renewal. In striking contrast, these genes are normalized in the presence of the EVI1 mutant. Moreover, EVI1, but not the EVI1 mutant, seemingly deregulates these cellular processes by altering miRNA expression. In particular, the silencing of miRNA-124 by DNA methylation is associated with EVI1 expression, but not that of the EVI1 mutant, and appears to play a key role in the up-regulation of cell division in murine BM cells and in the hematopoietic cell line 32Dcl3. The results presented here demonstrate that EVI1 induces MDS in the mouse through two major pathways, both of which require the interaction of EVI1 with other factors: one, results from EVI1-Gata1 interaction, which deregulates erythropoiesis and leads to fatal anemia, whereas the other occurs by interaction of EVI1 with unidentified factors causing perturbation of the cell cycle and self-renewal, as a consequence of silencing miRNA-124 by EVI1 and, ultimately, ensues in BM failure.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2906858PMC
http://dx.doi.org/10.1073/pnas.1004297107DOI Listing

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