title: Targeting of the BLT2 in chronic myeloid leukemia inhibits leukemia stem/progenitor cell function.
abstract: Imatinib, a tyrosine kinase inhibitor (TKI) has significantly improved clinical outcome for chronic myeloid leukemia (CML) patients. However, patients develop resistance when the disease progresses to the blast phase (BP) and the mechanisms are not well understood. Here we show that BCR-ABL activates BLT2 in hematopoietic stem/progenitor cells to promote leukemogenesis and this involves the p53 signaling pathway. Compared to normal bone marrow (NBM), the mRNA and protein levels of BLT2 are significantly increased in BP-CML CD34(+) stem/progenitor cells. This is correlated with increasing BCR-ABL expression. In contrast, knockdown of BCR-ABL or inhibition of its tyrosine kinase activity decreases Blt2 protein level. BLT2 inhibition induces apoptosis, inhibits proliferation, colony formation and self-renewal capacity of CD34(+) cells from TKI-resistant BP-CML patients. Importantly, the inhibitory effects of BCR-ABL TKI on CML stem/progenitor cells are further enhanced upon combination with BLT2 inhibition. We further show that BLT2 activation selectively suppresses p53 but not Wnt or BMP-mediated luciferase activity and transcription. Our results demonstrate that BLT2 is a novel pathway activated by BCR-ABL and critically involved in the resistance of BP-CML CD34(+) stem/progenitors to TKIs treatment. Our findings suggest that BLT2 and p53 can serve as therapeutic targets for CML treatment.
authors.affiliation: Department of Laboratory Medicine, JingZhou Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Jingzhou, People's Republic of China.
authors.forename: Meifang
authors.initials: M
authors.lastname: Xiao
authors.affiliation: Department of Laboratory Medicine, JingZhou Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Jingzhou, People's Republic of China.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Ai
authors.affiliation: Department of Laboratory Medicine, JingZhou Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Jingzhou, People's Republic of China.
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Clinical Medicine, Medical School of Yangtze University, Jingzhou, People's Republic of China.
authors.forename: Pasupati
authors.initials: P
authors.lastname: Rajoria
authors.affiliation: Department of Clinical Medicine, Medical School of Yangtze University, Jingzhou, People's Republic of China.
authors.forename: Prakash
authors.initials: P
authors.lastname: Shahu
authors.affiliation: Department of Neurosurgery, JingZhou Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Jingzhou, People's Republic of China. Electronic address: lixiansongjz@hotmail.com.
authors.forename: Xiansong
authors.initials: X
authors.lastname: Li
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D000067492:RNAi Therapeutics; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C485878:LTB4R2 protein, human; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D018102:Receptors, Leukotriene B4; D016159:Tumor Suppressor Protein p53; D016044:Fusion Proteins, bcr-abl
keywords: BLT2; Bcr-Abl tyrosine kinase inhibitor; Chronic myeloid leukemia; p53