CDKIs p18INK4c and p57Kip2 are involved in quiescence of CML leukemic stem cells after treatment with TKI |
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Authors: | Dafne Moreno-Lorenzana Sócrates Avilés-Vazquez Miguel Angel Sandoval Esquivel Antonio Alvarado-Moreno Vianney Ortiz-Navarrete Héctor Torres-Martínez |
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Institution: | 1. Oncology Research Unit, Oncology Hospital, National Medical Center, Mexican Institute for Social Security, Mexico City, Mexico;2. Molecular Biomedicine Department, CINVESTAV, Mexico City, Mexico;3. Thrombosis Haemostasia and Atherogenesis Research Unit, Mexican Institute for Social Security, Mexico City, Mexico;4. Molecular Biomedicine Department, CINVESTAV, Mexico City, Mexico;5. Department of Hip Surgery, Villa Coapa General Hospital, Mexican Institute for Social Security, Mexico City, Mexico |
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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 p18INK4c and p57Kip2 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 p18INK4c and p57Kip2 nuclear location. The differences in p18INK4cand p57Kip2activities 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. |
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Keywords: | chronic myeloid leukemia cyclin dependent kinase inhibitors and tirosine kinase inhibitors leukemic stem cells |
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