Glucocorticoids enhance the antileukemic activity of FLT3 inhibitors in FLT3-mutant acute myeloid leukemia
Autor: | Pinyi Lu, Longgui Chen, Barbara A. Miller, Zhongming Zhao, Charyguly Annageldiyev, Melat T. Gebru, Christopher M. Dower, Jennifer M. Atkinson, Arati Sharma, Megan M. Young, Zhenyuan Tang, Hong Gang Wang, Lijun Zhang, David F. Claxton, Yuka Imamura Kawasawa, Zhenqiu Liu |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Anti-Inflammatory Agents Drug resistance Biochemistry Dexamethasone chemistry.chemical_compound Mice 0302 clinical medicine hemic and lymphatic diseases Tumor Cells Cultured Medicine Myeloid Neoplasia Bcl-2-Like Protein 11 Gene Expression Regulation Leukemic Myeloid leukemia hemic and immune systems Drug Synergism Hematology Neoplasm Proteins Leukemia Myeloid Acute 030220 oncology & carcinogenesis Neoplastic Stem Cells FLT3 Inhibitor Glucocorticoid medicine.drug Programmed cell death Immunology Antineoplastic Agents 03 medical and health sciences Downregulation and upregulation Animals Humans Computer Simulation Benzothiazoles Selection Genetic Glucocorticoids Protein Kinase Inhibitors Quizartinib Inflammation business.industry Phenylurea Compounds Cell Biology Minimal residual disease Xenograft Model Antitumor Assays 030104 developmental biology chemistry fms-Like Tyrosine Kinase 3 Drug Resistance Neoplasm Cancer research Myeloid Cell Leukemia Sequence 1 Protein business Apoptosis Regulatory Proteins Transcriptome |
Zdroj: | Blood |
Popis: | FLT3 is a frequently mutated gene that is highly associated with a poor prognosis in acute myeloid leukemia (AML). Despite initially responding to FLT3 inhibitors, most patients eventually relapse with drug resistance. The mechanism by which resistance arises and the initial response to drug treatment that promotes cell survival is unknown. Recent studies show that a transiently maintained subpopulation of drug-sensitive cells, so-called drug-tolerant "persisters" (DTPs), can survive cytotoxic drug exposure despite lacking resistance-conferring mutations. Using RNA sequencing and drug screening, we find that treatment of FLT3 internal tandem duplication AML cells with quizartinib, a selective FLT3 inhibitor, upregulates inflammatory genes in DTPs and thereby confers susceptibility to anti-inflammatory glucocorticoids (GCs). Mechanistically, the combination of FLT3 inhibitors and GCs enhances cell death of FLT3 mutant, but not wild-type, cells through GC-receptor–dependent upregulation of the proapoptotic protein BIM and proteasomal degradation of the antiapoptotic protein MCL-1. Moreover, the enhanced antileukemic activity by quizartinib and dexamethasone combination has been validated using primary AML patient samples and xenograft mouse models. Collectively, our study indicates that the combination of FLT3 inhibitors and GCs has the potential to eliminate DTPs and therefore prevent minimal residual disease, mutational drug resistance, and relapse in FLT3-mutant AML. |
Databáze: | OpenAIRE |
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