Two TransformingC-RAFGerm-Line Mutations Identified in Patients with Therapy-Related Acute Myeloid Leukemia

Armin Zebisch, Philipp B. Staber, Ali Delavar, Claudia Bodner, Karin Hiden, Katja Fischereder, Manickam Janakiraman, Werner Linkesch, Holger W. Auner, Werner Emberger, Christian Windpassinger, Michael G. Schimek (+3 others)
2006 Cancer Research  
Mutations leading to activation of the RAF-mitogen-activated protein kinase/extracellular signal-regulated (ERK) kinase (MEK)-ERK pathway are key events in the pathogenesis of human malignancies. In a screen of 82 acute myeloid leukemia (AML) samples, 45 (55%) showed activated ERK and thus were further analyzed for mutations in B-RAF and C-RAF. Two C-RAF germ-line mutations, S427G and I448V, were identified in patients with therapy-related AML in the absence of alterations in RAS and FLT3. Both
more » ... exchanges were located within the kinase domain of C-RAF. In vitro and in vivo kinase assays revealed significantly increased activity for S427G C-RAF but not for I448V C-RAF. The involvement of the S427G C-RAF mutation in constitutive activation of ERK was further confirmed through demonstration of activating phosphorylations on C-RAF, MEK, and ERK in neoplastic cells, but not in nonneoplastic cells. Transformation and survival assays showed oncogenic and antiapoptotic properties for both mutations. Screening healthy individuals revealed a <1/400 frequency of these mutations and, in the case of I448V, inheritance was observed over three generations with another mutation carrier suffering from cancer. Taken together, these data are the first to relate C-RAF mutations to human malignancies. As both mutations are of germ-line origin, they might constitute a novel tumor-predisposing factor. (Cancer Res 2006; 66(7): 3401-8)
doi:10.1158/0008-5472.can-05-0115 pmid:16585161 fatcat:stvxjw7tqbesdlq7uxvirc3l6a