Novel AF1q/MLLT11 favorably affects imatinib resistance and cell survival in chronic myeloid leukemia
Autor: | Peng Li, Yihua Pang, Fei Lu, Jingru Zhang, Xin Dong, Chunyan Ji, Min Ji, Wei Li, Daoxin Ma, Jingjing Ye, Shaolei Zang |
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Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Cancer Research medicine.drug_class Cell Survival Immunology CD34 Fusion Proteins bcr-abl Antigens CD34 Apoptosis Tyrosine-kinase inhibitor Article 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Cell Line Tumor Leukemia Myelogenous Chronic BCR-ABL Positive Proto-Oncogene Proteins hemic and lymphatic diseases medicine Humans lcsh:QH573-671 Protein Kinase Inhibitors neoplasms biology business.industry lcsh:Cytology CD44 Myeloid leukemia Imatinib Cell Biology Neoplasm Proteins 030104 developmental biology medicine.anatomical_structure Hyaluronan Receptors Drug Resistance Neoplasm 030220 oncology & carcinogenesis biology.protein Cancer research Imatinib Mesylate Bone marrow business K562 Cells Tyrosine kinase medicine.drug |
Zdroj: | Cell Death and Disease, Vol 9, Iss 9, Pp 1-13 (2018) Cell Death & Disease |
ISSN: | 2041-4889 |
Popis: | Tyrosine kinase inhibitor treatment of chronic myeloid leukemia (CML) has demonstrated beneficial effects. However, resistance to tyrosine kinase inhibitors and disease relapse are still a challenge for CML therapy. In this study, we analyzed bone marrow samples from 149 CML patients and 15 control donors, and investigated the affect of AF1q on CML cell survival and engraftment in vitro and in vivo. We found that AF1q/MLLT11 expression was significantly upregulated in CML patients, especially in CD34+ CML cells. Elevated AF1q expression was associated with disease progression. Knockdown of AF1q enhanced imatinib sensitivity, induced apoptosis, and suppressed growth in CML cells. Moreover, AF1q deficiency sensitized CD34+ CML cells to imatinib. In contrast, upregulation of AF1q promoted cell survival, protected CML cells from imatinib-induced apoptosis, and increased engraftment of CML cells in vivo. We further identified a positive correlation between AF1q and CD44 expression in chronic phase CML patients and CD34+ CML cells. Importantly, AF1q contributes to imatinib-resistance in CML by regulating the expression of CD44. These findings reveal a novel BCR-ABL-independent pathway, AF1q/CD44, involves imatinib resistance in CML, thus representing a potential therapeutic target for imatinib-resistant CML patients. |
Databáze: | OpenAIRE |
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