Zinc-finger transcription factor slug contributes to the survival advantage of chronic myeloid leukemia cells.
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.
Mancini
Manuela
M
Department of Hematology and Oncology Lorenzo e Ariosto Seràgnoli, University of Bologna-Medical School, Via Massarenti 9, 40138-Bologna, Italy. mancini_manu@yahoo.com <mancini_manu@yahoo.com>
Petta
Sara
S
Iacobucci
Ilaria
I
Salvestrini
Valentina
V
Barbieri
Enza
E
Santucci
Maria Alessandra
MA
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*
D000970:Antineoplastic Agents; D001549:Benzamides; D015820:Cadherins; D010879:Piperazines; D011743:Pyrimidines; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl