Department of Hematology and Oncology Lorenzo e Ariosto Seràgnoli, University of Bologna-Medical School, Via Massarenti 9, 40138-Bologna, Italy.
Cell Signal. 2010 Aug;22(8):1247-53. doi: 10.1016/j.cellsig.2010.04.002. Epub 2010 Apr 11.
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.
Slug 是一种与蜗牛相关的锌指转录因子，在胚胎发育过程中间质细胞的迁移和癌细胞向侵袭表型的进展中发挥作用，在 Bcr-Abl 相关白血病的发病机制中发挥特定而关键的作用。在这里，我们报告 Slug 的过度表达与 Bcr-Abl 相关，这取决于 210 融合蛋白的酪氨酸激酶 (TK) 活性。Slug 的过度表达是由转录事件驱动的，最终通过转录后机制进行整合，导致蛋白质稳定，并至少部分受到 ERK1/2 丝裂原活化蛋白激酶 (MAPK) 的调节。它通过抑制促凋亡的 Puma 来促进白血病祖细胞的抗凋亡作用。此外，Slug 是由 Bcr-Abl 点突变驱动的白血病祖细胞对伊马替尼 (IM) 耐药的组成部分，特别是 T315I。与野生型 (wt) 或突变构象的 p210 Bcr-Abl TK 相关的 Slug 过度表达会导致细胞表面的 E-cadherin（β-catenin 的底物）显著减少。总之，我们的结果表明，Slug 在涉及 CML 祖细胞长期存活和对 IM 耐药的复杂网络中发挥核心作用。
