BCR/ABL-dependent VEGF gene expression: proposed signaling pathways.

Activation of Ras and PI3-kinase by BCR/ABL leads to MAPK signaling (Raf, MEK, ERK) and to activation of signaling molecules downstream of PI3-kinase. Based on results obtained with Ton.B210-X cells and primary CML-derived cells, it is hypothesized that VEGF induction by BCR/ABL is mediated through sequential activation of PI3-kinase, phosphoinositide-dependent kinase 1 (PDK1), Akt, mTOR, and p70 S6 kinase. As a result, the transcription factor HIF-1α is up-regulated. HIF-1, in turn, binds to HRE sites within the VEGF promoter and transcriptionally activates the VEGF gene.