Oncogenic heterogeneous nuclear ribonucleoprotein D-like modulates the growth and imatinib response of human chronic myeloid leukemia CD34+ cells via pre-B-cell leukemia homeobox 1
Oncogenic heterogeneous nuclear ribonucleoprotein D-like modulates the growth and imatinib response of human chronic myeloid leukemia CD34+ cells via pre-B-cell leukemia homeobox 1
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致癌异质核核糖核蛋白 D 样通过前 B 细胞白血病同源盒 1 调节人慢性粒细胞白血病 CD34 细胞的生长和伊马替尼反应
DOI：
10.1038/s41388-019-0998-9
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发表时间：
2020-01-01
期刊：
影响因子：
8
通讯作者：
Zhao, Yun
中科院分区：
文献类型：
--
作者：
Ji, Dehuan;Zhang, Pengshan;Zhao, Yun
慢性粒细胞白血病（CML）起源于获得BCR-ABL融合基因的正常造血干细胞，特异性BCR-ABL抑制剂（例如，伊马替尼甲磺酸盐，IM）已经极大地改善了患者管理。然而，一些患者仍然遭受复发和耐药性，这促使更好地了解CML干/祖细胞的生长/存活机制。本研究探讨了异质核核糖核蛋白D样（HNRPDL）在慢性粒细胞白血病细胞中的作用及其机制。首先，HNRPDL过表达促进小鼠BaF 3细胞体外生长，诱导小鼠白血病发生，BCR-ABL共表达可增强HNRPDL的促增殖作用;反之，HNRPDL沉默抑制CML CD 34+细胞集落形成细胞（CFC）的生成，减弱BCR-ABL诱导的白血病发生。此外，HNRPDL调节K562细胞的伊马替尼反应，并且HNRPDL沉默使CML CD 34+细胞对伊马替尼治疗敏感。机制上，我们发现HNRPDL通过与前B细胞白血病同源框1（PBX 1）3 '非翻译区（3'-UTR）的特异性基序（ACUAGC）结合来维持PBX 1 mRNA的稳定性。PBX 1在CML CD 34+细胞中的表达显著高于对照细胞，PBX沉默抑制CML细胞的生长并使其对伊马替尼治疗敏感。相反，PBX 1的过表达提高了正常造血CD 34+细胞的CFC产生，并“拯救”了HNRPDL沉默诱导的生长抑制和伊马替尼致敏。总之，我们的数据表明，HNRPDL转化造血细胞和一个新的HNRPDL/PBX 1轴在人CML CD 34+细胞中起着重要作用。
Chronic myeloid leukemia (CML) originates from normal hematopoietic stem cells acquiring BCR-ABL fusion gene, specific BCR-ABL inhibitors (e.g., imatinib mesylate, IM) have greatly improved patient management. However, some patients are still suffering from relapse and drug resistance, which urges better understanding of the growth/survival mechanisms of CML stem/progenitor cells. In the present study, the role and its underlying mechanism of heterogeneous nuclear ribonucleoprotein D-like (HNRPDL) in CML cells were investigated. Firstly, overexpression of HNRPDL promoted the growth of murine BaF3 cells in vitro and induced leukemia in vivo, which was enhanced by co-expression of BCR-ABL. Conversely, HNRPDL silencing inhibited colony-forming cell (CFC) production of CML CD34+cells and attenuated BCR-ABL induced leukemia. In addition, HNRPDL modulated imatinib response of K562 cells and HNRPDL silencing sensitized CML CD34+cells to imatinib treatment. Mechanistically, we found the stability of pre-B-cell leukemia homeobox 1 (PBX1) mRNA was sustained by HNRPDL through its binding to a specific motif (ACUAGC) in 3'-untranslated region (3'-UTR) of PBX1. The expression of PBX1 was significantly higher in CML CD34+cells than that in control cells and PBX silencing inhibited the growth of CML cells and sensitized them to imatinib treatment. In contrast, overexpression of PBX1 elevated the CFC production of normal hematopoietic CD34+cells and "rescued" HNRPDL silencing induced growth inhibition and imatinib sensitization. Taken together, our data have demonstrated that HNRPDL transforms hematopoietic cells and a novel HNRPDL/PBX1 axis plays an important role in human CML CD34+cells.