title: CDKIs p18(INK4c) and p57(Kip2) are involved in quiescence of CML leukemic stem cells after treatment with TKI.
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.
authors.affiliation: a Oncology Research Unit , Oncology Hospital, National Medical Center , Mexican Institute for Social Security , Mexico City , Mexico.|b Molecular Biomedicine Department , CINVESTAV , Mexico City , Mexico.
authors.forename: Dafne
authors.initials: D
authors.lastname: Moreno-Lorenzana
authors.affiliation: a Oncology Research Unit , Oncology Hospital, National Medical Center , Mexican Institute for Social Security , Mexico City , Mexico.
authors.forename: Sócrates
authors.initials: S
authors.lastname: Avilés-Vazquez
authors.affiliation: a Oncology Research Unit , Oncology Hospital, National Medical Center , Mexican Institute for Social Security , Mexico City , Mexico.
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Sandoval Esquivel
authors.affiliation: c Thrombosis Haemostasia and Atherogenesis Research Unit , Mexican Institute for Social Security , Mexico City , Mexico.
authors.forename: Antonio
authors.initials: A
authors.lastname: Alvarado-Moreno
authors.affiliation: b Molecular Biomedicine Department , CINVESTAV , Mexico City , Mexico.
authors.forename: Vianney
authors.initials: V
authors.lastname: Ortiz-Navarrete
authors.affiliation: d Department of Hip Surgery , Villa Coapa General Hospital , Mexican Institute for Social Security , Mexico City , Mexico.
authors.forename: Héctor
authors.initials: H
authors.lastname: Torres-Martínez
authors.affiliation: e Department of Hematology , La Raza Medical Center , Mexican Institute for Social Security , Mexico City , Mexico.
authors.forename: Manuel
authors.initials: M
authors.lastname: Ayala-Sánchez
authors.affiliation: a Oncology Research Unit , Oncology Hospital, National Medical Center , Mexican Institute for Social Security , Mexico City , Mexico.
authors.forename: Héctor
authors.initials: H
authors.lastname: Mayani
authors.affiliation: a Oncology Research Unit , Oncology Hospital, National Medical Center , Mexican Institute for Social Security , Mexico City , Mexico.
authors.forename: Antonieta
authors.initials: A
authors.lastname: Chavez-Gonzalez
mesh_terms: D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000378:metabolism*; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000378:metabolism*; D000069439:Dasatinib / Q000494:pharmacology; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D016192:Resting Phase, Cell Cycle / Q000187:drug effects
chemical_list: D050763:Cyclin-Dependent Kinase Inhibitor p18; D050761:Cyclin-Dependent Kinase Inhibitor p57; D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate; D000069439:Dasatinib
keywords: chronic myeloid leukemia; cyclin dependent kinase inhibitors and tirosine kinase inhibitors; leukemic stem cells