An essential pathway links FLT3-ITD, HCK and CDK6 in acute myeloid leukemia
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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
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
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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