Gehr Family Center for Leukemia Research, Hematology Malignancies and Stem Cell Transplantation Institute, City of Hope Medical Center, Duarte, CA, USA.
Department of Immuno-Oncology, City of Hope Medical Center, Duarte, CA, USA.
Leukemia. 2021 Aug;35(8):2285-2298. doi: 10.1038/s41375-021-01166-9. Epub 2021 Feb 15.
We report here on a novel pro-leukemogenic role of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) that interferes with microRNAs (miRNAs) biogenesis in acute myeloid leukemia (AML) blasts. We showed that FLT3-ITD interferes with the canonical biogenesis of intron-hosted miRNAs such as miR-126, by phosphorylating SPRED1 protein and inhibiting the "gatekeeper" Exportin 5 (XPO5)/RAN-GTP complex that regulates the nucleus-to-cytoplasm transport of pre-miRNAs for completion of maturation into mature miRNAs. Of note, despite the blockage of "canonical" miRNA biogenesis, miR-155 remains upregulated in FLT3-ITD+ AML blasts, suggesting activation of alternative mechanisms of miRNA biogenesis that circumvent the XPO5/RAN-GTP blockage. MiR-155, a BIC-155 long noncoding (lnc) RNA-hosted oncogenic miRNA, has previously been implicated in FLT3-ITD+ AML blast hyperproliferation. We showed that FLT3-ITD upregulates miR-155 by inhibiting DDX3X, a protein implicated in the splicing of lncRNAs, via p-AKT. Inhibition of DDX3X increases unspliced BIC-155 that is then shuttled by NXF1 from the nucleus to the cytoplasm, where it is processed into mature miR-155 by cytoplasmic DROSHA, thereby bypassing the XPO5/RAN-GTP blockage via "non-canonical" mechanisms of miRNA biogenesis.
我们在此报告了 FMS 样酪氨酸激酶 3 内部串联重复（FLT3-ITD）的一个新的促白血病作用，该作用干扰了急性髓系白血病（AML）blasts 中的 microRNAs（miRNAs）生物发生。我们表明，FLT3-ITD 通过磷酸化 SPRED1 蛋白并抑制“守门员”Exportin 5（XPO5）/RAN-GTP 复合物来干扰内含子宿主 miRNA（如 miR-126）的典型生物发生，该复合物调节 pre-miRNAs 的核质转运，以完成成熟为成熟的 miRNAs。值得注意的是，尽管“经典”miRNA 生物发生受阻，但 miR-155 在 FLT3-ITD+AMLblasts 中仍然上调，表明激活了绕过 XPO5/RAN-GTP 阻断的 miRNA 生物发生的替代机制。miR-155 是 BIC-155 长非编码（lnc）RNA 宿主致癌 miRNA，先前已被牵连到 FLT3-ITD+AMLblast 过度增殖中。我们表明，FLT3-ITD 通过抑制 DDX3X 来上调 miR-155，DDX3X 是一种参与 lncRNA 剪接的蛋白质，通过 p-AKT 抑制。DDX3X 的抑制增加了未剪接的 BIC-155，然后由 NXF1 从核转运到细胞质，在细胞质 DROSHA 中加工成成熟的 miR-155，从而绕过 XPO5/RAN-GTP 阻断，通过 miRNA 生物发生的“非经典”机制。
