Research Papers:
An essential pathway links FLT3-ITD, HCK and CDK6 in acute myeloid leukemia
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Abstract
Sophie Lopez1,2,3,4, Edwige Voisset1,2,3,4,5, Julie C. Tisserand1,2,3,4, Cyndie Mosca1,2,3,4, Thomas Prebet2, David Santamaria6, Patrice Dubreuil1,2,3,4, Paulo De Sepulveda1,2,3,4
1Inserm, Cancer Research Center of Marseille (CRCM), U1068, Marseille, France
2Institut Paoli-Calmettes (IPC), Marseille, France
3Aix-Marseille University, UM 105, Marseille, France
4CNRS, UMR7258, Marseille, France
5Present address: Department of Medical and Molecular Genetics, King's College London, Faculty of Life Sciences and Medicine, London, United Kingdom
6CNIO, Experimental Oncology Group, Madrid, Spain
Correspondence to:
Paulo De Sepulveda, email: [email protected]
Keywords: AML, protein kinase, oncogene, signaling, palbociclib, SRC
Received: November 24, 2015 Accepted: May 25, 2016 Published: June 13, 2016
ABSTRACT
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.
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PII: 9965