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

Sophie Lopez; Edwige Voisset; Julie C. Tisserand; Cyndie Mosca; Thomas Prebet; David Santamaria; Patrice Dubreuil; Paulo De Sepulveda

doi:10.18632/oncotarget.9965

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Research Papers:

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

Sophie Lopez, Edwige Voisset, Julie C. Tisserand, Cyndie Mosca, Thomas Prebet, David Santamaria, Patrice Dubreuil and Paulo De Sepulveda _

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Oncotarget. 2016; 7:51163-51173. https://doi.org/10.18632/oncotarget.9965

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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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Research Papers:

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

Abstract