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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

Abstract

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.

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Acknowledgements

This work was supported by National Natural Science Foundation of China (Nos. 31771579, 31371392 to YZ, 81400113 to HZ, 81500119 to XZ, and 81800151 to WM), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and the Innovation Capability Development Project of Jiangsu Province (No. BM2015004).

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DJ, PZ, and WM performed most experimental work and PZ initiated the experimental study. YF, WX, YW, and XZ provided critical technical supports. HZ and YZ conceived the project and designed the study. H.Z. also supervised the quality of the clinical samples. YZ, HZ, DJ, PZ, and WM wrote the manuscript. All authors have read and approved this manuscript.

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Correspondence to Haixia Zhou or Yun Zhao.

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Ji, D., Zhang, P., Ma, W. et al. 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. Oncogene 39, 443–453 (2020). https://doi.org/10.1038/s41388-019-0998-9

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