Cobll1 is linked to drug resistance and blastic transformation in chronic myeloid leukemia

• Published in: Leukemia 2017-07, Vol.31 (7), p.1532-1539
• Main Authors: Han, S H, Kim, S-H, Kim, H-J, Lee, Y, Choi, S-Y, Park, G, Kim, D-H, Lee, A, Kim, J, Choi, J-M, Kim, Y, Myung, K, Kim, H, Kim, D-W
• Format: Article
• Language: English
• Subjects: 13/1; 13/31; 42/109; 42/70; 631/67/1990/283/1896; 692/699/1541/1990/283/1896; 82/51; 96/100; 96/95; Apoptosis; BCR-ABL protein; Biomarkers; Blast Crisis; Blast resistance; Cancer Research; Care and treatment; CD34 antigen; Cell Line, Tumor; Cell survival; Chronic myeloid leukemia; Cobl protein; Critical Care Medicine; Drug resistance; Drug Resistance, Neoplasm; Embryogenesis; Embryonic growth stage; Enzyme inhibitors; Fusion Proteins, bcr-abl - physiology; Hematology; Hematopoiesis; Humans; I-kappa B Kinase - physiology; Inhibitors; Intensive; Internal Medicine; Kinases; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - mortality; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Medicine; Medicine & Public Health; MicroRNAs - physiology; Myeloid leukemia; NF-kappa B - physiology; NF-κB protein; Oncology; original-article; Protein-tyrosine kinase; Pyrimidines - therapeutic use; Signaling; Stem cells; Survival; Therapeutic targets; Transcription Factors - physiology; Tyrosine; Zebrafish
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2017.72

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.