Dasatinib inhibits leukaemic cell survival by decreasing PRH/Hhex phosphorylation resulting in increased repression of VEGF signalling genes.

ABSTRACT

The PRH/Hhex transcription factor represses multiple genes in the VEGF signalling pathway (VSP) to inhibit myeloid cell survival. Protein kinase CK2 phosphorylates PRH and counteracts the inhibitory effect of this protein on cell survival by blocking the repression of VSP genes. Here we show that the BCR-ABL/Src kinase inhibitor dasatinib decreases PRH phosphorylation and increases PRH-dependent repression of Vegf and Vegfr-1. Moreover in the absence of PRH, dasatinib does not inhibit cell survival as effectively as in PRH expressing cells. Thus the re-establishment of gene control by PRH is in part responsible for the therapeutic effects of dasatinib.