title: Cobll1 is linked to drug resistance and blastic transformation in chronic myeloid leukemia.
abstract: Drug resistance to BCR-ABL1 tyrosine kinase inhibitor (TKI) and disease progression to blast crisis (BC) are major clinical problems in chronic myeloid leukemia (CML); however, underlying mechanisms governing this process remain to be elucidated. Here, we report Cordon-bleu protein-like 1 (Cobll1) as a distinct molecular marker associated with drug resistance as well as progression to BC. In detail, Cobll1 increases IKKγ stability, leading to NF-κB activation and reduction of nilotinib-dependent apoptosis, suggesting Cobll1-mediated NF-κB could be involved in drug resistance. Recently, NF-κB signalling has been highlighted as a core mechanism for chronic phase (CP)-BC progression, stem cell survival and tyrosine kinase inhibitor resistance. We also demonstrated that high expression of Cobll1 confers drug resistance to tyrosine kinase inhibitors in CML cell line as well as patient samples. The analysis of large sets of primary CML samples (n=90) shows that Cobll1 expression is dramatically increased in BC but not in CP, which is correlated with a poor survival rate (P=0.002). Moreover, our studies show that Cobll1 is highly expressed in CD34+primitive stem cell populations, and the zebrafish paralog Cobll1b is important for normal hematopoiesis during embryonic development. Based on these results, we propose that Cobll1 is a novel biomarker and potential therapeutic target for CML-BC.
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Republic of Korea.
authors.forename: S H
authors.initials: SH
authors.lastname: Han
authors.affiliation: Leukemia Research Institute, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: S-H
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Republic of Korea.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Center for Genomic Integrity Institute for Basic Science (IBS), Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
authors.forename: Y
authors.identifier: 0000-0001-7919-9048
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Leukemia Research Institute, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: S-Y
authors.initials: SY
authors.lastname: Choi
authors.affiliation: Department of Pathology, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: G
authors.initials: G
authors.lastname: Park
authors.affiliation: Department of Life Science, College of Natural Sciences, Hanyang University, Seoul, Republic of Korea.
authors.forename: D-H
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Life Systems, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: A
authors.initials: A
authors.lastname: Lee
authors.affiliation: Department of Life Systems, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: J
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Life Science, College of Natural Sciences, Hanyang University, Seoul, Republic of Korea.
authors.forename: J-M
authors.initials: JM
authors.lastname: Choi
authors.affiliation: Department of Life Systems, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Y
authors.identifier: 0000-0001-8574-4938
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Center for Genomic Integrity Institute for Basic Science (IBS), Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
authors.forename: K
authors.initials: K
authors.lastname: Myung
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Republic of Korea.|Center for Neuroscience Imaging Research (CNIR), Institute for Basic Science (IBS), Suwon, Republic of Korea.
authors.forename: H
authors.initials: H
authors.lastname: Kim
authors.affiliation: Leukemia Research Institute, The Catholic University of Korea, Seoul, Republic of Korea.|Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: D-W
authors.initials: DW
authors.lastname: Kim
mesh_terms: D001752:Blast Crisis; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000502:physiology; D006801:Humans; D051550:I-kappa B Kinase / Q000502:physiology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D035683:MicroRNAs / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology; D011743:Pyrimidines / Q000627:therapeutic use; D014157:Transcription Factors / Q000502:physiology*
chemical_list: C581634:BCR-ABL1 fusion protein, human; C584084:COBLL1 protein, human; C554214:MIRN424 microrna, human; C545473:MIRN503 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D011743:Pyrimidines; D014157:Transcription Factors; D016044:Fusion Proteins, bcr-abl; D051550:I-kappa B Kinase; C498826:nilotinib