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Rbm15 Modulates Notch-Induced Transcriptional Activation and Affects Myeloid Differentiation

机译：Rbm15调节Notch诱导的转录激活并影响骨髓分化。

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RBM15 is the fusion partner with MKL in the t(1;22) translocation of acute megakaryoblastic leukemia. To understand the role of the RBM15-MKL1 fusion protein in leukemia, we must understand the normal functions of RBM15 and MKL. Here, we show a role for Rbm15 in myelopoiesis. Rbm15 is expressed at highest levels in hematopoietic stem cells and at more moderate levels during myelopoiesis of murine cell lines and primary murine cells. Decreasing Rbm15 levels with RNA interference enhances differentiation of the 32DWT18 myeloid precursor cell line. Conversely, enforced expression of Rbm15 inhibits 32DWT18 differentiation. We show that Rbm15 alters Notch-induced HES1 promoter activity in a cell type-specific manner. Rbm15 inhibits Notch-induced HES1 transcription in nonhematopoietic cells but stimulates this activity in hematopoietic cell lines, including 32DWT18 and human erythroleukemia cells. Moreover, the N terminus of Rbm15 coimmunoprecipitates with RBPJκ, a critical factor in Notch signaling, and the Rbm15 N terminus has a dominant negative effect, impairing activation of HES1 promoter activity by full-length-Rbm15. Thus, Rbm15 is differentially expressed during hematopoiesis and may act to inhibit myeloid differentiation in hematopoietic cells via a mechanism that is mediated by stimulation of Notch signaling via RBPJκ.
机译： RBM15 是 MKL 在急性巨核细胞白血病t（1; 22）易位中的融合伴侣。要了解RBM15-MKL1融合蛋白在白血病中的作用，我们必须了解RBM15和MKL的正常功能。在这里，我们显示了Rbm15在骨髓生成中的作用。 Rbm15在造血干细胞中最高水平表达，在鼠细胞系和原代鼠细胞骨髓生成过程中以中等水平表达。通过RNA干扰降低Rbm15水平可增强32DWT18髓样前体细胞系的分化。相反，Rbm15的强制表达抑制了32DWT18的分化。我们显示，Rbm15以细胞类型特异性方式改变Notch诱导的 HES1 启动子活性。 Rbm15抑制Notch诱导的非造血细胞中的 HES1 转录，但刺激造血细胞系（包括32DWT18和人红白血病细胞）中的这种活性。此外，Rbm15的N末端与Notch信号的关键因子RBPJκ共沉淀，而Rbm15 N末端具有显性的负作用，从而削弱了全长Rbm15对 HES1 启动子活性的激活。因此，Rbm15在造血过程中差异表达，并可能通过通过RBPJκ刺激Notch信号传导介导的机制来抑制造血细胞中的髓样分化。

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