Chronic Myeloid Leukemia (CML) is a cancer caused by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood.

During the past few years, drug resistance to BCR-ABL1 tyrosine kinase inhibitor (TKI) and disease progression to blast crisis (BC) have become major clinical problems in chronic myeloid leukemia. However, underlying mechanisms governing this process remain to be elucidated.

The joint-research team led by Prof. Hong Tae KIM (Center for Neuroscience Imaging Research of SKKU), Prof. Dong Wook KIM (The Catholic University of Korea), and Gyeong Jae MYEONG (Ulsan National Institute of Science and Technology, UNIST) reported 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. The team 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, their 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, they proposed that Cobll1 is a novel biomarker and potential therapeutic target for CML-BC.

Prof. Hong Tae KIM of SKKU mentioned “Another piece of the puzzle of the CML process mechanism has been placed by indicating that Cobll1 is one of the key molecules that regulate resistance to TKI. I believe our studies have implications for developing novel therapeutic strategies in diagnosis and treatment of CML Cobll1 can be a therapeutic target to inhibit the signaling cascade of CML progression, as well as a biomarker to detect phase progression in CML patients.”

The result of the research was published in Luekemia, the No.1 journal in the field of Luekemia and sister journal of the Nature, on Feb 24^th.