Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/8876
An essential pathway links FLT3-ITD, HCK and CDK6 in acute myeloid leukemia
Oncotarget. 2016;7 (32):51163-51173.
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.
Animals | Cell Line, Tumor | Cyclin-Dependent Kinase 6 | Gene Expression Regulation, Leukemic | Humans | Leukemia, Myeloid, Acute | Mice | Mice, Inbred C57BL | Mice, Knockout | Mutation | Proto-Oncogene Proteins c-hck | Signal Transduction | Tandem Repeat Sequences | fms-Like Tyrosine Kinase 3