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Chronic myelogenous leukemia

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

Leukemia volume 31, pages 1532–1539 (2017)Cite this article

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A Corrigendum to this article was published on 11 April 2017

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.

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References

  1. Deininger MW, Goldman JM, Melo JV . The molecular biology of chronic myeloid leukemia. Blood 2000; 96: 3343–3356.

    CAS  PubMed  Google Scholar 

  2. Bocchia M, Gentili S, Abruzzese E, Fanelli A, Iuliano F, Tabilio A et al. Effect of a p210 multipeptide vaccine associated with imatinib or interferon in patients with chronic myeloid leukaemia and persistent residual disease: a multicentre observational trial. Lancet 2005; 365: 657–662.

    Article  CAS  Google Scholar 

  3. Kumar C, Purandare AV, Lee FY, Lorenzi MV . Kinase drug discovery approaches in chronic myeloproliferative disorders. Oncogene 2009; 28: 2305–2313.

    Article  CAS  Google Scholar 

  4. Sloma I, Jiang X, Eaves AC, Eaves CJ . Insights into the stem cells of chronic myeloid leukemia. Leukemia 2010; 24: 1823–1833.

    Article  CAS  Google Scholar 

  5. Melo JV, Barnes DJ . Chronic myeloid leukaemia as a model of disease evolution in human cancer. Nat Rev Cancer 2007; 7: 441–453.

    Article  CAS  Google Scholar 

  6. O’Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003; 348: 994–1004.

    Article  Google Scholar 

  7. Frelin C, Imbert V, Griessinger E, Peyron AC, Rochet N, Philip P et al. Targeting NF-kappaB activation via pharmacologic inhibition of IKK2-induced apoptosis of human acute myeloid leukemia cells. Blood 2005; 105: 804–811.

    Article  CAS  Google Scholar 

  8. Druker BJ, Guilhot F, O'Brien SG, Gathmann I, Kantarjian H, Gattermann N et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006; 355: 2408–2417.

    Article  CAS  Google Scholar 

  9. Masiello D, Gorospe G, Yang AS . The occurrence and management of fluid retention associated with TKI therapy in CML, with a focus on dasatinib. J Hematol Oncol 2009; 2: 1.

    Article  Google Scholar 

  10. Deininger MW, Druker BJ . Specific targeted therapy of chronic myelogenous leukemia with imatinib. Pharmacol Rev 2003; 55: 401–423.

    Article  CAS  Google Scholar 

  11. Radich J . Structure, function, and resistance in chronic myeloid leukemia. Cancer Cell 2014; 26: 305–306.

    Article  CAS  Google Scholar 

  12. Soverini S, Colarossi S, Gnani A, Rosti G, Castagnetti F, Poerio A et al. Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: by the GIMEMA Working Party on Chronic Myeloid Leukemia. Clin Cancer Res 2006; 12: 7374–7379.

    Article  CAS  Google Scholar 

  13. Gambacorti-Passerini C, Barni R, le Coutre P, Zucchetti M, Cabrita G, Cleris L et al. Role of α1 acid glycoprotein in the in vivo resistance of human BCR-ABL+ leukemic cells to the Abl inhibitor STI571. J Natl Cancer Inst 2000; 92: 1641–1650.

    Article  CAS  Google Scholar 

  14. Donato NJ, Wu JY, Stapley J, Gallick G, Lin H, Arlinghaus R et al. BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood 2003; 101: 690–698.

    Article  CAS  Google Scholar 

  15. Mahon F-X, Belloc F, Lagarde V, Chollet C, Moreau-Gaudry F, Reiffers J et al. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood 2003; 101: 2368–2373.

    Article  CAS  Google Scholar 

  16. Von Bubnoff N, Peschel C, Duyster J . Resistance of Philadelphia-chromosome positive leukemia towards the kinase inhibitor imatinib (STI571, Glivec): a targeted oncoprotein strikes back. Leukemia 2003; 17: 829–838.

    Article  CAS  Google Scholar 

  17. Ito T, Kwon HY, Zimdahl B, Congdon KL, Blum J, Lento WE et al. Regulation of myeloid leukaemia by the cell-fate determinant Musashi. Nature 2010; 466: 765–768.

    Article  CAS  Google Scholar 

  18. Nagase T, Ishikawa K-i, Suyama M, Kikuno R, Hirosawa M, Miyajima N et al. Prediction of the coding sequences of unidentified human genes. XIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res 1999; 6: 63–70.

    Article  CAS  Google Scholar 

  19. Gordon GJ, Bueno R, Sugarbaker DJ . Genes associated with prognosis after surgery for malignant pleural mesothelioma promote tumor cell survival in vitro. BMC Cancer 2011; 11: 169.

    Article  Google Scholar 

  20. Mancina RM, Burza MA, Maglio C, Pirazzi C, Sentinelli F, Incani M et al. The COBLL1 C allele is associated with lower serum insulin levels and lower insulin resistance in overweight and obese children. Diabetes Metab Res Rev 2013; 29: 413–416.

    Article  CAS  Google Scholar 

  21. Chung YJ, Kim TM, Kim DW, Namkoong H, Kim HK, Ha SA et al. Gene expression signatures associated with the resistance to imatinib. Leukemia 2006; 20: 1542–1550.

    Article  CAS  Google Scholar 

  22. Kim TM, Ha SA, Kim HK, Yoo J, Kim S, Yim SH et al. Gene expression signatures associated with the in vitro resistance to two tyrosine kinase inhibitors, nilotinib and imatinib. Blood Cancer J 2011; 1: e32.

    Article  Google Scholar 

  23. Goh H-G, Kim Y-J, Kim D-W, Kim H-J, Kim S-H, Jang S-E et al. Previous best responses can be re-achieved by resumption after imatinib discontinuation in patients with chronic myeloid leukemia: implication for intermittent imatinib therapy. Leuk Lymphoma 2009; 50: 944–951.

    Article  CAS  Google Scholar 

  24. Hughes T, Deininger M, Hochhaus A, Branford S, Radich J, Kaeda J et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 2006; 108: 28–37.

    Article  CAS  Google Scholar 

  25. Branford S, Fletcher L, Cross NC, Müller MC, Hochhaus A, Kim D-W et al. Desirable performance characteristics for BCR-ABL measurement on an international reporting scale to allow consistent interpretation of individual patient response and comparison of response rates between clinical trials. Blood 2008; 112: 3330–3338.

    Article  CAS  Google Scholar 

  26. Karin M, Cao Y, Greten FR, Li ZW . NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer 2002; 2: 301–310.

    Article  CAS  Google Scholar 

  27. Li Q, Verma IM . NF-kappaB regulation in the immune system. Nat Rev Immunol 2002; 2: 725–734.

    Article  CAS  Google Scholar 

  28. Hayden MS, Ghosh S . Signaling to NF-kappaB. Genes Dev 2004; 18: 2195–2224.

    Article  CAS  Google Scholar 

  29. Oliver KM, Garvey JF, Ng CT, Veale DJ, Fearon U, Cummins EP et al. Hypoxia activates NF-kappaB-dependent gene expression through the canonical signaling pathway. Antioxid Redox Signal 2009; 11: 2057–2064.

    Article  CAS  Google Scholar 

  30. Baeuerle PA, Baichwal VR . NF-kappa B as a frequent target for immunosuppressive and anti-inflammatory molecules. Adv Immunol 1997; 65: 111–137.

    Article  CAS  Google Scholar 

  31. Duncan EA, Goetz CA, Stein SJ, Mayo KJ, Skaggs BJ, Ziegelbauer K et al. IkappaB kinase beta inhibition induces cell death in Imatinib-resistant and T315I dasatinib-resistant BCR-ABL+ cells. Mol Cancer Ther 2008; 7: 391–397.

    Article  CAS  Google Scholar 

  32. Duckett CS, Thompson CB . CD30-dependent degradation of TRAF2: implications for negative regulation of TRAF signaling and the control of cell survival. Genes Dev 1997; 11: 2810–2821.

    Article  CAS  Google Scholar 

  33. Shi M, Deng W, Bi E, Mao K, Ji Y, Lin G et al. TRIM30 alpha negatively regulates TLR-mediated NF-kappa B activation by targeting TAB2 and TAB3 for degradation. Nat Immunol 2008; 9: 369–377.

    Article  CAS  Google Scholar 

  34. Ahmed N, Zeng M, Sinha I, Polin L, Wei WZ, Rathinam C et al. The E3 ligase Itch and deubiquitinase Cyld act together to regulate Tak1 and inflammation. Nat Immunol 2011; 12: 1176–1183.

    Article  CAS  Google Scholar 

  35. Shibata Y, Oyama M, Kozuka-Hata H, Han X, Tanaka Y, Gohda J et al. p47 negatively regulates IKK activation by inducing the lysosomal degradation of polyubiquitinated NEMO. Nat Commun 2012; 3: 1061.

    Article  Google Scholar 

  36. Tao T, Cheng C, Ji Y, Xu G, Zhang J, Zhang L et al. Numbl inhibits glioma cell migration and invasion by suppressing TRAF5-mediated NF-kappaB activation. Mol Biol Cell 2012; 23: 2635–2644.

    Article  CAS  Google Scholar 

  37. Corbin AS, Agarwal A, Loriaux M, Cortes J, Deininger MW, Druker BJ . Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. J Clin Invest 2011; 121: 396–409.

    Article  CAS  Google Scholar 

  38. Zhao C, Xiu Y, Ashton J, Xing L, Morita Y, Jordan CT et al. Noncanonical NF-kappaB signaling regulates hematopoietic stem cell self-renewal and microenvironment interactions. Stem Cells 2012; 30: 709–718.

    Article  CAS  Google Scholar 

  39. Stainier DY, Kontarakis Z, Rossi A . Making sense of anti-sense data. Dev Cell 2015; 32: 7–8.

    Article  CAS  Google Scholar 

  40. Espín-Palazón R, Stachura DL, Campbell CA, García-Moreno D, Del Cid N, Kim AD et al. Proinflammatory signaling regulates hematopoietic stem cell emergence. Cell 2014; 159: 1070–1085.

    Article  Google Scholar 

  41. Radich JP, Dai H, Mao M, Oehler V, Schelter J, Druker B et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci USA 2006; 103: 2794–2799.

    Article  CAS  Google Scholar 

  42. Cramer K, Nieborowska-Skorska M, Koptyra M, Slupianek A, Penserga ETP, Eaves CJ et al. BCR/ABL and other kinases from chronic myeloproliferative disorders stimulate single-strand annealing, an unfaithful DNA double-strand break repair. Cancer Res 2008; 68: 6884–6888.

    Article  CAS  Google Scholar 

  43. San José-Enériz E, Román-Gómez J, Jiménez-Velasco A, Garate L, Martin V, Cordeu L et al. MicroRNA expression profiling in Imatinib-resistant chronic myeloid leukemia patients without clinically significant ABL1-mutations. Mol Cancer 2009; 8: 1.

    Article  Google Scholar 

  44. Babashah S, Sadeghizadeh M, Tavirani MR, Farivar S, Soleimani M . Aberrant microRNA expression and its implications in the pathogenesis of leukemias. Cell Oncol 2012; 35: 317–334.

    Article  CAS  Google Scholar 

  45. Forrest AR, Kanamori-Katayama M, Tomaru Y, Lassmann T, Ninomiya N, Takahashi Y et al. Induction of microRNAs, mir-155, mir-222, mir-424 and mir-503, promotes monocytic differentiation through combinatorial regulation. Leukemia 2010; 24: 460–466.

    Article  CAS  Google Scholar 

  46. Hershkovitz-Rokah O, Modai S, Pasmanik-Chor M, Toren A, Shomron N, Raanani P et al. Restoration of miR-424 suppresses BCR–ABL activity and sensitizes CML cells to imatinib treatment. Cancer Lett 2015; 360: 245–256.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the Korea Leukemia Bank for providing the CML samples. This work was supported by IBS-R015-D1, the New Faculty Fund (1.150054) of UNIST and a National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (NRF-2013M3A9B8031236). We thank the Korea Leukemia Bank for biomaterial banking and analysis (NRF-2013M3A9B8031236).

Author contributions

Seung Hun Han, Soo-Hyun Kim, Yoonsung Lee, Hyoung-June Kim, Soo-Young Choi, Gyeongsin Park, Do-Hyun Kim, Aram Lee, Jongmin Kim, Je-Min Choi, Yonghwan Kim, Kyungjae Myung, Hongtae Kim and Dong-Wook Kim designed and carried out experiment. Kyungjae Myung, Hongtae Kim and Dong-Wook Kim supervised the project and wrote the manuscript.

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Author notes

  1. S H Han, H-J Kim and Y Lee: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biological Sciences, Sungkyunkwan University, Suwon, Republic of Korea

    S H Han, H-J Kim & H Kim

  2. Leukemia Research Institute, The Catholic University of Korea, Seoul, Republic of Korea

    S-H Kim, S-Y Choi & D-W Kim

  3. Center for Genomic Integrity Institute for Basic Science (IBS), Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea

    Y Lee & K Myung

  4. Department of Pathology, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea

    G Park

  5. Department of Life Science, College of Natural Sciences, Hanyang University, Seoul, Republic of Korea

    D-H Kim & J-M Choi

  6. Department of Life Systems, Sookmyung Women’s University, Seoul, Republic of Korea

    A Lee, J Kim & Y Kim

  7. Center for Neuroscience Imaging Research (CNIR), Institute for Basic Science (IBS), Suwon, Republic of Korea

    H Kim

  8. Department of Hematology, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea

    D-W Kim

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Han, S., Kim, SH., Kim, HJ. et al. Cobll1 is linked to drug resistance and blastic transformation in chronic myeloid leukemia. Leukemia 31, 1532–1539 (2017). https://doi.org/10.1038/leu.2017.72

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