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    SF3B1 mutation promotes c-MYC protein stability and modulation of SF3B1 constitutes an effective therapeutic strategy in chronic lymphocytic leukemia.

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    Authors
    Han, Qimei
    Issue Date
    2019-10
    URI
    http://hdl.handle.net/10675.2/622699
    
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    Abstract
    The splicing factor, SF3B1, is frequently mutated and causes shorter disease progression free survival and inferior overall survival in chronic lymphocytic leukemia (CLL). However, how mutant SF3B1-induced alternative splicing events contribute to inferior prognosis remains elusive. In this study, we demonstrated that SF3B1 mutation causes aberrant splicing of PPP2R5A mRNA by the usage of a cryptic 3’ splice site. Consequently, a frameshift is induced during translation and multiple pre-mature stop codons are created, leading to its degradation through a process known as nonsense-mediated decay (NMD). The aberrant splicing and downregulation of PPP2R5A at both mRNA and protein levels were confirmed in primary CLL samples and exogenous mutant SF3B1 overexpression models. Furthermore, the decreased expression of PPP2R5A preserves c-MYC serine62 phosphorylation and increases c-MYC protein abundance by promoting its protein stability. Knocking down of PPP2R5A in CLL cells retains the phosphorylation of c-MYC at serine62 and increases c-MYC level, which further confirms its essential role in increased c-MYC stability. SF3B1 has been suggested as a potential therapeutic target in multiple malignancies. We demonstrated that SF3B1 modulator sudemycin D6 (SD6) effectively suppresses CLL cell growth and induces apoptosis both in vitro and in vivo. RNA sequencing analysis revealed a significant increase in global intron retention (IR) in SD6-treated CLL cells. Pathway analysis of the genes associated with increased IR suggested that B-cell receptor (BCR) and PI3K signaling pathways were among the most important pathways being deregulated by SD6. The increase in IR was inversely correlated with a decrease in mRNA and protein levels of a number of key molecules in the BCR/PI3K pathways. SD6 also induced a time-dependent exon-skipping event in anti-apoptotic MCL1 mRNA and resulted in significant down-regulation of another anti-apoptotic gene TRAF1, thus collectively contributing to the SD6-induced apoptosis. Furthermore, SD6 overcame the pro-survival and pro-growth signals and synergized with established CLL therapies, such as ibrutinib, idelalisib, and venetoclax, to induce apoptosis in primary CLL cells, particularly when co-cultured with bone marrow stromal cells and T-cell-derived cytokines. Collectively, these results provide a strong rationale for future clinical development of spliceosome modulators and potential combination therapies for the treatment of CLL.
    Affiliation
    Biomedical Sciences
    Description
    Embargoed until 10/11/2021
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    Theses and Dissertations

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