Zinc-finger transcription factor slug contributes to the survival advantage of chronic myeloid leukemia cells

Abstract

Slug, a Snail-related zinc-finger transcription factor implicated in the increased motility of mesenchymal cells during embryonic development and progression of cancer cells towards an invasive phenotype, plays a specific and critical role in the pathogenesis of Bcr-Abl-associated leukemias. Here we report that Slug over-expression associated with Bcr-Abl is conditional upon the tyrosine kinase (TK) activity of 210 fusion protein. Slug over-expression is driven by transcriptional events eventually integrated by post-transcriptional mechanisms leading to protein stabilization and is at least partly regulated by the ERK1/2 mitogen-activated protein kinase (MAPK). It contributes to apoptosis resistance of leukemic progenitors through the repression of pro-apoptotic Puma. Moreover, Slug is a component of leukemic progenitor resistance to imatinib mesylate (IM) driven by Bcr-Abl point mutations and, in particular, by T315I. Slug over-expression associated with p210 Bcr-Abl TK either in the wild type (wt) or mutated conformation results in a significant reduction of E- cadherin, the substrate of Beta catenin at cell membranes. In conclusion, our results suggest that Slug has a central role in a complex network involved in prolonged survival and IM resistance of CML progenitors.