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

作者：Zhang, JinFang^*; Liu, XiaoLi; Yin, ChangXin; Zong, Sa

来源：Experimental Hematology, 2022, 108: 46-54.

DOI：10.1016/j.exphem.2022.01.004

• NUCLEAR RIBONUCLEOPROTEIN K
• CHRONIC MYELOID-LEUKEMIA
• DRUG-RESISTANCE
• HNRNP K
• PROLIFERATION
• IRRADIATION

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). Expres-sion 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 imati-nib sensitivity of these tumor cells and decreased in vivo tumor burden in a xenograft model system as evi-denced 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 path-way may play a role in shaping imatinib resistance in Ph+ ALL cells.

• 单位
  南方医科大学; 广东省人民医院