An essential pathway links FLT3-ITD, HCK and CDK6 in acute myeloid leukemia.
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.
Inserm, Cancer Research Center of Marseille (CRCM), U1068, Marseille, France.|Institut Paoli-Calmettes (IPC), Marseille, France.|Aix-Marseille University, UM 105, Marseille, France.|CNRS, UMR7258, Marseille, France.
Sophie
S
Lopez
Inserm, Cancer Research Center of Marseille (CRCM), U1068, Marseille, France.|Institut Paoli-Calmettes (IPC), Marseille, France.|Aix-Marseille University, UM 105, Marseille, France.|CNRS, UMR7258, Marseille, France.|Present address: Department of Medical and Molecular Genetics, King's College London, Faculty of Life Sciences and Medicine, London, United Kingdom.
Edwige
E
Voisset
Inserm, Cancer Research Center of Marseille (CRCM), U1068, Marseille, France.|Institut Paoli-Calmettes (IPC), Marseille, France.|Aix-Marseille University, UM 105, Marseille, France.|CNRS, UMR7258, Marseille, France.
Julie C
JC
Tisserand
Inserm, Cancer Research Center of Marseille (CRCM), U1068, Marseille, France.|Institut Paoli-Calmettes (IPC), Marseille, France.|Aix-Marseille University, UM 105, Marseille, France.|CNRS, UMR7258, Marseille, France.
Cyndie
C
Mosca
Institut Paoli-Calmettes (IPC), Marseille, France.
Thomas
T
Prebet
CNIO, Experimental Oncology Group, Madrid, Spain.
David
D
Santamaria
Inserm, Cancer Research Center of Marseille (CRCM), U1068, Marseille, France.|Institut Paoli-Calmettes (IPC), Marseille, France.|Aix-Marseille University, UM 105, Marseille, France.|CNRS, UMR7258, Marseille, France.
Patrice
P
Dubreuil
Inserm, Cancer Research Center of Marseille (CRCM), U1068, Marseille, France.|Institut Paoli-Calmettes (IPC), Marseille, France.|Aix-Marseille University, UM 105, Marseille, France.|CNRS, UMR7258, Marseille, France.
Paulo
P
De Sepulveda
D000818:Animals; D045744:Cell Line, Tumor; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics* / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D051572:Proto-Oncogene Proteins c-hck / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D020080:Tandem Repeat Sequences; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics* / Q000378:metabolism
C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; C496631:HCK protein, human; D051572:Proto-Oncogene Proteins c-hck; C495911:CDK6 protein, human; C495912:Cdk6 protein, mouse; D051361:Cyclin-Dependent Kinase 6
AML; SRC; oncogene; palbociclib; protein kinase; signaling