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Rigshospitalet - a part of Copenhagen University Hospital
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In vivo RNAi screening for the identification of oncogenes and tumor suppressors in acute myeloid leukemia

Research output: Book/ReportPh.D. thesisResearch

  1. Mutant CEBPA directly drives the expression of the targetable tumor-promoting factor CD73 in AML

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. The splicing factor RBM25 controls MYC activity in acute myeloid leukemia

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. The functional consequences of intron retention: Alternative splicing coupled to NMD as a regulator of gene expression

    Research output: Contribution to journalJournal articleResearchpeer-review

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Acute myeloid leukemia (AML) is an aggressive malignancy characterized by uncontrolled expansion of immature myeloid cells in the hematopoietic tissues. Alternative splicing and epigenetic regulation are two mechanisms implicated in the pathogenesis of AML. In order to identify the essential splicing factors or epigenetic regulators for AML maintenance, we used a pool-based shRNA in vivo screens in a mouse model of human CEBPA mutated AML. Through these approaches, we found the splicing factor RBM25, and the histone methyltransferase SUV39H1 are of functional importance in AML progression. Characterization of RBM25 indicates that low expression of RBM25 promotes expansion of both murine and human leukemic cells. Mechanistic studies show that RBM25 regulate splicing dysregulation of several crucial genes in AML. In particular, we demonstrate that RBM25 knockdown leads to the accumulation of the anti-apoptotic isoform BCL‐xL, and consequently RBM25 knockdown cells are partially resistant to ABT‐263 mediated inhibition of BCL‐xL. All in all, the newly identified tumor suppressor gene RBM25 has great clinical values as a potential predictive biomarker. By systematical analysis of SUV39H1 using in vivo murine AML models and in vitro human leukemic cell lines, we demonstrated that low expression of Suv39H1 leads to ablated tumor progression and the growth inhibition of leukemic cells. This might take place via partial differentiation of the leukemic cells. Thus, we provide evidence for a role of SUV39H1 as a tumor‐promoting factor in AML, pointing out it as a potential target for therapeutic strategies of the disease. In summary, our findings demonstrate that splicing factor RBM25 and epigenetic regulator SUV39H1 are vital for AML progression, and thus they both may forward for future therapeutic intervention.
Original languageEnglish
PublisherEget Forlag
Number of pages156
Publication statusPublished - 12 Apr 2016

ID: 48277836