1. CDKIs p18(INK4c) and p57(Kip2) are involved in quiescence of CML leukemic stem cells after treatment with TKI.
- Author
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Moreno-Lorenzana D, Avilés-Vazquez S, Sandoval Esquivel MA, Alvarado-Moreno A, Ortiz-Navarrete V, Torres-Martínez H, Ayala-Sánchez M, Mayani H, and Chavez-Gonzalez A
- Subjects
- Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Dasatinib pharmacology, Gene Expression Regulation, Leukemic drug effects, Humans, Imatinib Mesylate pharmacology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells metabolism, Protein Transport drug effects, Resting Phase, Cell Cycle drug effects, Cell Cycle Checkpoints drug effects, Cyclin-Dependent Kinase Inhibitor p18 metabolism, Cyclin-Dependent Kinase Inhibitor p57 metabolism, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Neoplastic Stem Cells pathology, Protein Kinase Inhibitors pharmacology
- Abstract
Chronic Myeloid Leukemia (CML) is sustained by a small population of cells with stem cell characteristics known as Leukemic Stem Cells that are positive to BCR-ABL fusion protein, involved with several abnormalities in cell proliferation, expansion, apoptosis and cell cycle regulation. Current treatment options for CML involve the use of Tirosine Kinase Inhibitor (Imatinib, Nilotinib and Dasatinib), that efficiently reduce proliferation proliferative cells but do not kill non proliferating CML primitive cells that remain and contributes to the persistence of the disease. In order to understand the role of Cyclin Dependent Kinase Inhibitors in CML LSC permanence after TKI treatment, in this study we analyzed cell cycle status, the levels of several CDKIs and the subcellular localization of such molecules in different CML cell lines, as well as primary CD34(+)CD38(-)lin(-) LSC and HSC. Our results demonstrate that cellular location of p18(INK4c) and p57(Kip2) seems to be implicated in the antiproliferative activity of Imatinib and Dasatinib in CML cells and also suggest that the permanence of quiescent stem cells after TKI treatment could be associated with a decrease in p18(INK4c) and p57(Kip2) nuclear location. The differences in p18(INK4c)and p57(Kip2)activities in CML and normal stem cells suggest a different cell cycle regulation and provide a platform that could be considered in the development of new therapeutic options to eliminate LSC.
- Published
- 2016
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