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An essential pathway links FLT3-ITD, HCK and CDK6 in acute myeloid leukemia
CDK4/CDK6 and RB proteins drive the progression through the G1 phase of the cell cycle. In acute myeloid leukemia (AML), the activity of the CDK/Cyclin D complex is increased. The mechanism involved is unknown, as are the respective roles played by CDK4 or CDK6 in this process. Here, we report that...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5239466/ https://www.ncbi.nlm.nih.gov/pubmed/27323399 http://dx.doi.org/10.18632/oncotarget.9965 |
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author | Lopez, Sophie Voisset, Edwige Tisserand, Julie C. Mosca, Cyndie Prebet, Thomas Santamaria, David Dubreuil, Patrice Sepulveda, Paulo De |
author_facet | Lopez, Sophie Voisset, Edwige Tisserand, Julie C. Mosca, Cyndie Prebet, Thomas Santamaria, David Dubreuil, Patrice Sepulveda, Paulo De |
author_sort | Lopez, Sophie |
collection | PubMed |
description | CDK4/CDK6 and RB proteins drive the progression through the G1 phase of the cell cycle. In acute myeloid leukemia (AML), the activity of the CDK/Cyclin D complex is increased. The mechanism involved is unknown, as are the respective roles played by CDK4 or CDK6 in this process. Here, we report that AML cells carrying FLT3-ITD mutations are dependent on CDK6 for cell proliferation while CDK4 is not essential. We showed that FLT3-ITD signaling is responsible for CDK6 overexpression, through a pathway involving the SRC-family kinase HCK. Accordingly, FLT3-ITD failed to transform primary hematopoietic progenitor cells from Cdk6−/− mice. Our results demonstrate that CDK6 is the primary target of CDK4/CDK6 inhibitors in FLT3-ITD positive AML. Furthermore, we delineate an essential protein kinase pathway -FLT3/HCK/CDK6- in the context of AML with FLT3-ITD mutations. |
format | Online Article Text |
id | pubmed-5239466 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-52394662017-01-24 An essential pathway links FLT3-ITD, HCK and CDK6 in acute myeloid leukemia Lopez, Sophie Voisset, Edwige Tisserand, Julie C. Mosca, Cyndie Prebet, Thomas Santamaria, David Dubreuil, Patrice Sepulveda, Paulo De Oncotarget Research Paper CDK4/CDK6 and RB proteins drive the progression through the G1 phase of the cell cycle. In acute myeloid leukemia (AML), the activity of the CDK/Cyclin D complex is increased. The mechanism involved is unknown, as are the respective roles played by CDK4 or CDK6 in this process. Here, we report that AML cells carrying FLT3-ITD mutations are dependent on CDK6 for cell proliferation while CDK4 is not essential. We showed that FLT3-ITD signaling is responsible for CDK6 overexpression, through a pathway involving the SRC-family kinase HCK. Accordingly, FLT3-ITD failed to transform primary hematopoietic progenitor cells from Cdk6−/− mice. Our results demonstrate that CDK6 is the primary target of CDK4/CDK6 inhibitors in FLT3-ITD positive AML. Furthermore, we delineate an essential protein kinase pathway -FLT3/HCK/CDK6- in the context of AML with FLT3-ITD mutations. Impact Journals LLC 2016-06-13 /pmc/articles/PMC5239466/ /pubmed/27323399 http://dx.doi.org/10.18632/oncotarget.9965 Text en Copyright: © 2016 Lopez et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Lopez, Sophie Voisset, Edwige Tisserand, Julie C. Mosca, Cyndie Prebet, Thomas Santamaria, David Dubreuil, Patrice Sepulveda, Paulo De An essential pathway links FLT3-ITD, HCK and CDK6 in acute myeloid leukemia |
title | An essential pathway links FLT3-ITD, HCK and CDK6 in acute myeloid leukemia |
title_full | An essential pathway links FLT3-ITD, HCK and CDK6 in acute myeloid leukemia |
title_fullStr | An essential pathway links FLT3-ITD, HCK and CDK6 in acute myeloid leukemia |
title_full_unstemmed | An essential pathway links FLT3-ITD, HCK and CDK6 in acute myeloid leukemia |
title_short | An essential pathway links FLT3-ITD, HCK and CDK6 in acute myeloid leukemia |
title_sort | essential pathway links flt3-itd, hck and cdk6 in acute myeloid leukemia |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5239466/ https://www.ncbi.nlm.nih.gov/pubmed/27323399 http://dx.doi.org/10.18632/oncotarget.9965 |
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