title: Tyrosine kinase inhibitors induce mesenchymal stem cell-mediated resistance in BCR-ABL+ acute lymphoblastic leukemia.
abstract: Tyrosine kinase inhibitors (TKIs) are used as a frontline therapy for BCR-ABL(+) acute lymphoblastic leukemia (ALL). However, resistance to TKI therapy arises rapidly, and its underlying molecular mechanisms are poorly understood. In this study, we identified a novel cascade of events initiated by TKIs and traversing through mesenchymal stem cells (MSCs) to leukemic cells, leading to resistance. MSCs exposed to TKIs acquired a new functional status with the expression of genes encoding for chemo-attractants, adhesion molecules, and prosurvival growth factors, and this priming enabled leukemic cells to form clusters underneath the MSCs. This cluster formation was associated with the protection of ALL cells from therapy as leukemic cells switched from BCR-ABL signaling to IL-7R/Janus kinase signaling to survive in the MSC milieu. Our findings illustrate a novel perspective in the evolution of TKI resistance and provide insights for advancing the treatment of BCR-ABL(+) ALL.
authors.affiliation: Department of Laboratory Medicine and the Center for Stem Cell and Developmental Biology, and.
authors.forename: Saradhi
authors.initials: S
authors.lastname: Mallampati
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Leng
authors.affiliation: Department of Laboratory Medicine and the Center for Stem Cell and Developmental Biology, and Department of Oncology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China;
authors.forename: Haiqing
authors.initials: H
authors.lastname: Ma
authors.affiliation: Department of Laboratory Medicine and the Center for Stem Cell and Developmental Biology, and.
authors.forename: Jianfang
authors.initials: J
authors.lastname: Zeng
authors.affiliation: Department of Laboratory Medicine and the Center for Stem Cell and Developmental Biology, and.
authors.forename: June
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Laboratory Medicine and the Center for Stem Cell and Developmental Biology, and Department of Hematology, The Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China;
authors.forename: Haiying
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: Kevin
authors.initials: K
authors.lastname: Lin
authors.affiliation: Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: Yue
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Laboratory Medicine and the Center for Stem Cell and Developmental Biology, and Multiple Myeloma Treatment Center and Department of Hematology, The First Affiliated Hospital of Medical College, Zhejiang University, Hangzhou, Zhejiang, China;
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Laboratory Medicine and the Center for Stem Cell and Developmental Biology, and.
authors.forename: Baohua
authors.initials: B
authors.lastname: Sun
authors.affiliation: Department of Pathology.
authors.forename: Yun
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Department of System Biology.
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Leukemia, Department of Stem Cell Transplantation, and.
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
authors.affiliation: Department of Leukemia, Department of Stem Cell Transplantation, and.
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: Ralph B
authors.initials: RB
authors.lastname: Arlinghaus
authors.affiliation: Multiple Myeloma Treatment Center and Department of Hematology, The First Affiliated Hospital of Medical College, Zhejiang University, Hangzhou, Zhejiang, China;
authors.forename: Zhen
authors.initials: Z
authors.lastname: Cai
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: Bingliang
authors.initials: B
authors.lastname: Fang
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX; Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY; and.
authors.forename: Haifa
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Laboratory Medicine and the Center for Stem Cell and Developmental Biology, and.
authors.forename: Xin
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Laboratory Medicine and the Center for Stem Cell and Developmental Biology, and.
authors.forename: Cheryl F
authors.initials: CF
authors.lastname: Hirsch-Ginsberg
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, TX.
authors.forename: Xiaolian
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: Anurag N
authors.initials: AN
authors.lastname: Paranjape
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: Sendurai A
authors.initials: SA
authors.lastname: Mani
authors.affiliation: Department of Stem Cell Transplantation, and.
authors.forename: Karen
authors.initials: K
authors.lastname: Clise-Dwyer
authors.affiliation: Department of Laboratory Medicine and the Center for Stem Cell and Developmental Biology, and.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Sun
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D016044:Fusion Proteins, bcr-abl