hnRNPK/Beclin1 signaling regulates autophagy to promote imatinib resistance in Philadelphia chromosome-positive acute lymphoblastic leukemia cells

• Published in: Experimental hematology Vol. 108; pp. 46 - 54
• Main Authors: Zhang, JinFang, Liu, XiaoLi, Yin, ChangXin, Zong, Sa
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.04.2022
• Subjects: Autophagy; Beclin-1 - genetics; Beclin-1 - metabolism; Cell Line, Tumor; Drug Resistance, Neoplasm; Heterogeneous-Nuclear Ribonucleoprotein K - genetics; Heterogeneous-Nuclear Ribonucleoprotein K - metabolism; Humans; Imatinib Mesylate - pharmacology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Signal Transduction - physiology
• ISSN: 0301-472X; 1873-2399
• DOI: 10.1016/j.exphem.2022.01.004

•Dysregulation of the hnRNPK/Beclin1 signaling axis is linked to enhanced resistance to imatinib in Ph+ acute lymphoblastic leukemia cells.•hnRNPK could regulate the mRNA expression level of Beclin1 in Ph+ acute lymphoblastic leukemia cell lines.•hnRNPK could shape imatinib resistance at least in part by enhancing autophagic activity.•hnRNPK is a key regulator of in vivo leukemia cell resistance to imatinib. This study sought to clarify the role of heterogeneous nuclear ribonucleoprotein K (hnRNPK) as a regulator of imatinib resistance in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Expression of hnRNPK was assessed in Ph+ ALL leukemia cells in vitro and in vivo, and imatinib susceptibility was assessed via CCK-8 assay. In cells in which hnRNPK levels had or had not been modulated, LC3Ⅰ/Ⅱ and mTOR/p-ERK/Beclin1 levels were assessed via Western blotting, while electron microscopy was used to evaluate autophagic vacuole formation. Interactions between hnRNPK and Beclin1 were assessed through an RNA binding protein immunoprecipitation assay. Imatinib-resistant Ph+ ALL cell lines and patient bone marrow samples exhibited significant hnRNPK overexpression. Knockdown of hnRNPK increased the imatinib sensitivity of these tumor cells and decreased in vivo tumor burden in a xenograft model system as evidenced by a reduction in tumor volume. Levels of LC3Ⅰ/Ⅱ and Beclin1, but not p-ERK and mTOR, were consistent with the regulatory activity of hnRNPK. Electron microscopy revealed that imatinib-resistant cells harbored significantly more autophagic vacuoles relative to wild-type cells, while hnRNPK knockdown reduced the number of these vacuoles. In an RNA-binding protein immunoprecipitation assay, anti-hnRNPK was able to precipitate the Beclin1 mRNA. These results suggest that the hnRNPK/Beclin1 signaling pathway may play a role in shaping imatinib resistance in Ph+ ALL cells.