title: The sensitivity of chronic myeloid leukemia CD34 cells to Bcr-Abl tyrosine kinase inhibitors is modulated by ceramide levels.
abstract: Despite BCR-ABL tyrosine kinase inhibitors (TKIs) improved outcome of patients with chronic myeloid leukemia (CML), resistance still develops when progresses to blast phase (BP). The mechanisms underlying resistance to TKIs are not well understood. In this study, we analyzed ceramide levels in CD34 cells derived from BP-CML patients and healthy donor bone marrow (BM) using liquid chromatography mass spectrometry. We found that ceramide level was significantly lower in BP-CML CD34 compared with normal BM counterparts. BP-CML CD34 ceramide(low) were more resistant to BCR-ABL TKIs compared to BP-CML CD34 ceramide(normal). Both mRNA and proteins levels of sphingomyelin synthase 1 and 2 are lower in BP-CML CD34 ceramide(low) compared to normal BM CD34 cells, suggesting that these two ceramide synthesis enzymes maybe the mechanism of how ceramide level is suppressed. Importantly, up-regulation of cellular ceramide level induces apoptosis of multiple CML cell lines and BP-CML CD34 progenitors. Combination of BCR-ABL TKIs with ceramide analog is synergistic in targeting BP-CML 34 progenitors. Collectively, our work provides evidence that down-regulation of ceramide level is involved in the resistance of BP-CML CD34 progenitors to TKIs treatment. Targeting ceramide metabolism together with BCR-ABL inhibition makes it an attractive addition to the armamentarium in BP-CML treatment.
authors.affiliation: Department of Oncology, JingZhou Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Jing Zhou, People's Republic of China.
authors.forename: Jiaqiao
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Oncology, JingZhou Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Jing Zhou, People's Republic of China.
authors.forename: June
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Oncology, JingZhou Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Jing Zhou, People's Republic of China.
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Jin
authors.affiliation: Department of Oncology, JingZhou Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Jing Zhou, People's Republic of China. Electronic address: wanhuihuisky@hotmail.com.
authors.forename: Huihui
authors.initials: H
authors.lastname: Wan
mesh_terms: D000328:Adult; D000368:Aged; D018952:Antigens, CD34; D001854:Bone Marrow Cells / Q000737:chemistry / Q000201:enzymology; D002460:Cell Line; D002518:Ceramides / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D017855:Transferases (Other Substituted Phosphate Groups) / Q000032:analysis; D014407:Tumor Cells, Cultured
chemical_list: D018952:Antigens, CD34; D002518:Ceramides; D047428:Protein Kinase Inhibitors; D016044:Fusion Proteins, bcr-abl; D017855:Transferases (Other Substituted Phosphate Groups); C070186:phosphatidylcholine-ceramide phosphocholine transferase
keywords: Bcr-Abl tyrosine kinase inhibitor; Ceramide; Chronic myeloid leukemia; Sphingomyelin synthase