Journal
ONCOTARGET
Volume 7, Issue 32, Pages 51163-51173Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.9965
Keywords
AML; protein kinase; oncogene; signaling; palbociclib; SRC
Categories
Funding
- La Ligue Contre le Cancer (Equipe labelisee)
- Fondation ARC pour la Recherche sur le Cancer
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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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