Internal Tandem Duplication in FLT3 Attenuates Proliferation and Regulates Resistance to the FLT3 Inhibitor AC220 by Modulating p21Cdkn1a and Pbx1 in Hematopoietic Cells
| العنوان: | Internal Tandem Duplication in FLT3 Attenuates Proliferation and Regulates Resistance to the FLT3 Inhibitor AC220 by Modulating p21Cdkn1a and Pbx1 in Hematopoietic Cells |
|---|---|
| المؤلفون: | Takeshi Taketani, Louis M. Pelus, Pratibha Singh, Jamiyan Purevsuren, Seiji Fukuda, Tomohiro Hirade, Seiji Yamaguchi, Mariko Abe, Chie Onishi |
| المصدر: | PLoS ONE PLoS ONE, Vol 11, Iss 7, p e0158290 (2016) |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | 0301 basic medicine, Physiology, Cell, lcsh:Medicine, Gene Expression, Hematologic Cancers and Related Disorders, Mice, Endocrinology, Cell Signaling, Animal Cells, hemic and lymphatic diseases, Medicine and Health Sciences, Cell Cycle and Cell Division, lcsh:Science, Multidisciplinary, Pre-B-Cell Leukemia Transcription Factor 1, Myeloid leukemia, hemic and immune systems, Hematology, Myeloid Leukemia, Haematopoiesis, Leukemia, medicine.anatomical_structure, Phenotype, Oncology, Tandem Repeat Sequences, Cell Processes, embryonic structures, Cytokines, Female, Signal transduction, Cellular Types, psychological phenomena and processes, Signal Transduction, Research Article, Cyclin-Dependent Kinase Inhibitor p21, Acute Myeloid Leukemia, Signal Inhibition, Bone Marrow Cells, Biology, Antibodies, 03 medical and health sciences, Growth Factors, Leukemias, medicine, Genetics, Animals, Humans, Cell Lineage, Gene Regulation, Benzothiazoles, Gene Silencing, Cell Proliferation, Homeodomain Proteins, Endocrine Physiology, Cell growth, Phenylurea Compounds, lcsh:R, Biology and Life Sciences, Cancers and Neoplasms, Cell Biology, medicine.disease, Hematopoietic Stem Cells, Cyclic AMP-Dependent Protein Kinases, body regions, Mice, Inbred C57BL, 030104 developmental biology, Gene Expression Regulation, fms-Like Tyrosine Kinase 3, Fms-Like Tyrosine Kinase 3, Cancer research, lcsh:Q, Bone marrow, Tumor Suppressor Protein p53, Gene Deletion, Transcription Factors |
| الوصف: | Internal tandem duplication (ITD) mutations in the Fms-related tyrosine kinase 3 (FLT3) gene (FLT3-ITD) are associated with poor prognosis in patients with acute myeloid leukemia (AML). Due to the development of drug resistance, few FLT3-ITD inhibitors are effective against FLT3-ITD+ AML. In this study, we show that FLT3-ITD activates a novel pathway involving p21Cdkn1a (p21) and pre-B cell leukemia transcription factor 1 (Pbx1) that attenuates FLT3-ITD cell proliferation and is involved in the development of drug resistance. FLT3-ITD up-regulated p21 expression in both mouse bone marrow c-kit+-Sca-1+-Lin- (KSL) cells and Ba/F3 cells. The loss of p21 expression enhanced growth factor-independent proliferation and sensitivity to cytarabine as a consequence of concomitantly enriching the S+G2/M phase population and significantly increasing the expression of Pbx1, but not Evi-1, in FLT3-ITD+ cells. This enhanced cell proliferation following the loss of p21 was partially abrogated when Pbx1 expression was silenced in FLT3-ITD+ primary bone marrow colony-forming cells and Ba/F3 cells. When FLT3-ITD was antagonized with AC220, a selective inhibitor of FLT3-ITD, p21 expression was decreased coincident with Pbx1 mRNA up-regulation and a rapid decline in the number of viable FLT3-ITD+ Ba/F3 cells; however, the cells eventually became refractory to AC220. Overexpressing p21 in FLT3-ITD+ Ba/F3 cells delayed the emergence of cells that were refractory to AC220, whereas p21 silencing accelerated their development. These data indicate that FLT3-ITD is capable of inhibiting FLT3-ITD+ cell proliferation through the p21/Pbx1 axis and that treatments that antagonize FLT3-ITD contribute to the subsequent development of cells that are refractory to a FLT3-ITD inhibitor by disrupting p21 expression. |
| تدمد: | 1932-6203 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ff74ca9969327202611795947bd182eb https://pubmed.ncbi.nlm.nih.gov/27387666 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....ff74ca9969327202611795947bd182eb |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19326203 |
|---|