LncRNA IRAIN overcomes imatinib resistance in chronic myeloid leukemia via NF-κB/CD44 pathway inhibition
Xijia Wang,
Yutong Hou,
Yizhu Lyu,
Jiayin Zhou,
Xin Zhang,
Mohammad Arian Hassani,
Dan Huang,
Zhijia Zhao,
Dong Zhou,
Fang Xie,
Xuehong Zhang,
Jinsong Yan
Affiliations
Xijia Wang
Department of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, the Second Hospital of Dalian Medical University, Dalian 116027, China; Liaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational Medicine, Blood Stem Cell Transplantation Institute, Dalian Key Laboratory of Hematology, Diamond Bay Institute of Hematology, the Second Hospital of Dalian Medical University, Dalian 116027, China
Yutong Hou
Department of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, the Second Hospital of Dalian Medical University, Dalian 116027, China
Yizhu Lyu
Department of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, the Second Hospital of Dalian Medical University, Dalian 116027, China
Jiayin Zhou
Department of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, the Second Hospital of Dalian Medical University, Dalian 116027, China; Liaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational Medicine, Blood Stem Cell Transplantation Institute, Dalian Key Laboratory of Hematology, Diamond Bay Institute of Hematology, the Second Hospital of Dalian Medical University, Dalian 116027, China
Xin Zhang
Department of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, the Second Hospital of Dalian Medical University, Dalian 116027, China; Liaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational Medicine, Blood Stem Cell Transplantation Institute, Dalian Key Laboratory of Hematology, Diamond Bay Institute of Hematology, the Second Hospital of Dalian Medical University, Dalian 116027, China
Mohammad Arian Hassani
Department of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, the Second Hospital of Dalian Medical University, Dalian 116027, China; Liaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational Medicine, Blood Stem Cell Transplantation Institute, Dalian Key Laboratory of Hematology, Diamond Bay Institute of Hematology, the Second Hospital of Dalian Medical University, Dalian 116027, China
Dan Huang
Department of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, the Second Hospital of Dalian Medical University, Dalian 116027, China; Liaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational Medicine, Blood Stem Cell Transplantation Institute, Dalian Key Laboratory of Hematology, Diamond Bay Institute of Hematology, the Second Hospital of Dalian Medical University, Dalian 116027, China
Zhijia Zhao
Department of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, the Second Hospital of Dalian Medical University, Dalian 116027, China
Dong Zhou
Department of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, the Second Hospital of Dalian Medical University, Dalian 116027, China
Fang Xie
Department of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, the Second Hospital of Dalian Medical University, Dalian 116027, China; Liaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational Medicine, Blood Stem Cell Transplantation Institute, Dalian Key Laboratory of Hematology, Diamond Bay Institute of Hematology, the Second Hospital of Dalian Medical University, Dalian 116027, China; Corresponding author
Xuehong Zhang
Center of Genome and Personalized Medicine, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning 116044, China; Corresponding author
Jinsong Yan
Department of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, the Second Hospital of Dalian Medical University, Dalian 116027, China; Liaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational Medicine, Blood Stem Cell Transplantation Institute, Dalian Key Laboratory of Hematology, Diamond Bay Institute of Hematology, the Second Hospital of Dalian Medical University, Dalian 116027, China; Department of Pediatric, Pediatric Oncology and Hematology Center of the Second Hospital of Dalian Medical University, Dalian, Liaoning 116027, China; Corresponding author
Summary: The development of tyrosine kinase inhibitors (TKIs) has revolutionarily increased the overall survival of patients with chronic myeloid leukemia (CML). However, drug resistance remains a major obstacle. Here, we demonstrated that a BCR-ABL1-independent long non-coding RNA, IRAIN, is constitutively expressed at low levels in CML, resulting in imatinib resistance. IRAIN knockdown decreased the sensitivity of CD34+ CML blasts and cell lines to imatinib, whereas IRAIN overexpression significantly increased sensitivity. Mechanistically, IRAIN downregulates CD44, a membrane receptor favorably affecting TKI resistance, by binding to the nuclear factor kappa B subunit p65 to reduce the expression of p65 and phosphorylated p65. Therefore, the demethylating drug decitabine, which upregulates IRAIN, combined with imatinib, formed a dual therapy strategy which can be applied to CML with resistance to TKIs.
