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Mutations of the human B-RAF gene are detected in f8% of cancer samples, primarily in cutaneous melanomas (70%). The most common mutation (90%) is a valine-to-glutamic acid mutation at residue 600 (V600E; formerly V599E according to previous nomenclature). Using a Cre/Lox approach, we have generated a conditional knock-in allele of V600E B-raf in mice. We show that widespread expression of V600E B-Raf cannot be tolerated in embryonic development, with embryos dying f7.5 dpc. Directed expression of mutant V600E B-Raf to somatic tissues using the IFN-inducible Mx1-Cre mouse strain induces a proliferative disorder and bone marrow failure with evidence of nonlymphoid neoplasia of the histiocytic type leading to death within 4 weeks of age. However, expression of mutant B-Raf does not alter the proliferation profile of all somatic tissues. In primary mouse embryonic fibroblasts, expression of endogenous V600E B-Raf induces morphologic transformation, increased cell proliferation, and loss of contact inhibition. Thus, V600E

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