Lopez Sophie, Voisset Edwige, Tisserand Julie C, Mosca Cyndie, Prebet Thomas, Santamaria David, Dubreuil Patrice, De Sepulveda Paulo
Inserm, Cancer Research Center of Marseille (CRCM), U1068, Marseille, France.
Institut Paoli-Calmettes (IPC), Marseille, France.
Oncotarget. 2016 Aug 9;7(32):51163-51173. doi: 10.18632/oncotarget.9965.
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.
细胞周期蛋白依赖性激酶4/6（CDK4/CDK6）和视网膜母细胞瘤（RB）蛋白驱动细胞周期G1期的进程。在急性髓系白血病（AML）中，CDK/细胞周期蛋白D复合物的活性增加。其涉及的机制尚不清楚，CDK4或CDK6在此过程中各自所起的作用也不清楚。在此，我们报告携带FLT3内部串联重复（FLT3-ITD）突变的AML细胞的增殖依赖于CDK6，而CDK4并非必需。我们表明，FLT3-ITD信号通过涉及SRC家族激酶HCK的途径导致CDK6过表达。因此，FLT3-ITD无法转化来自Cdk6基因敲除小鼠的原代造血祖细胞。我们的结果表明，在FLT3-ITD阳性AML中，CDK6是CDK4/CDK6抑制剂的主要靶点。此外，我们在具有FLT3-ITD突变的AML背景下描绘了一条重要的蛋白激酶途径——FLT3/HCK/CDK6。
