title: A therapeutically targetable mechanism of BCR-ABL-independent imatinib resistance in chronic myeloid leukemia.
abstract: Resistance to the BCR-ABL inhibitor imatinib mesylate (IM) poses a major problem for the treatment of chronic myeloid leukemia (CML). IM resistance often results from a secondary mutation in BCR-ABL that interferes with drug binding. However, in many instances, there is no mutation in BCR-ABL, and the basis of such BCR-ABL-independent IM resistance remains to be elucidated. To gain insight into BCR-ABL-independent IM resistance mechanisms, we performed a large-scale RNA interference screen and identified IM-sensitizing genes (IMSGs) whose knockdown renders BCR-ABL(+) cells IM-resistant. In these IMSG knockdown cells, RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling is sustained after IM treatment because of up-regulation of PRKCH, which encodes the protein kinase C (PKC) family member PKCη, an activator of CRAF. PRKCH is also up-regulated in samples from CML patients with BCR-ABL-independent IM resistance. Combined treatment with IM and trametinib, a U.S. Food and Drug Administration-approved MEK inhibitor, synergistically kills BCR-ABL(+) IMSG knockdown cells and prolongs survival in mouse models of BCR-ABL-independent IM-resistant CML. Finally, we showed that CML stem cells contain high levels of PRKCH, and this contributes to their intrinsic IM resistance. Combined treatment with IM and trametinib synergistically kills CML stem cells with negligible effect on normal hematopoietic stem cells. Collectively, our results identify a therapeutically targetable mechanism of BCR-ABL-independent IM resistance in CML and CML stem cells.
authors.affiliation: Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Leyuan
authors.initials: L
authors.lastname: Ma
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Shan
authors.affiliation: Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Bai
authors.affiliation: Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Liting
authors.initials: L
authors.lastname: Xue
authors.affiliation: Howard Hughes Medical Institute, Knight Cancer Institute, Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Eide
authors.affiliation: Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Jianhong
authors.initials: J
authors.lastname: Ou
authors.affiliation: Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA. Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Lihua J
authors.initials: LJ
authors.lastname: Zhu
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Lloyd
authors.initials: L
authors.lastname: Hutchinson
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Cerny
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA 30332, USA.
authors.forename: Hanna Jean
authors.initials: HJ
authors.lastname: Khoury
authors.affiliation: Virginia Tech Carilion Research Institute, Roanoke, VA 24016, USA. Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, VA 24061, USA.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Sheng
authors.affiliation: Howard Hughes Medical Institute, Knight Cancer Institute, Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Shaoguang
authors.initials: S
authors.lastname: Li
authors.affiliation: Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA. michael.green@umassmed.edu.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Green
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D052138:Genes, Neoplasm; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011493:Protein Kinase C / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D034741:RNA, Small Interfering / Q000378:metabolism; D016019:Survival Analysis; D015854:Up-Regulation / Q000187:drug effects; D048490:raf Kinases / Q000378:metabolism
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D034741:RNA, Small Interfering; D000068877:Imatinib Mesylate; C081975:protein kinase C eta; D016044:Fusion Proteins, bcr-abl; D048490:raf Kinases; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases