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

作者：Lopez Sophie; Voisset Edwige; Tisserand Julie C; Mosca Cyndie; Prebet Thomas; Santamaria David; Dubreuil Patrice; De Sepulveda Paulo^*

来源：Oncotarget, 2016, 7(32): 51163-51173.

DOI：10.18632/oncotarget.9965

• AML
• protein kinase
• oncogene
• signaling
• palbociclib
• SRC

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.

• 出版日期2016-8-9