Differential Effects of X-ALK Fusion Proteins on Proliferation, Transformation, and Invasion Properties of NIH3T3 Cells

Oncogene. 2004 Aug 12;23(36):6071-82. doi: 10.1038/sj.onc.1207813.

Abstract

Majority of anaplastic large-cell lymphomas (ALCLs) are associated with the t(2;5)(p23;q35) translocation, fusing the NPM (nucleophosmin) and ALK (anaplastic lymphoma kinase) genes (NPM-ALK). Recent studies demonstrated that ALK may also be involved in variant translocations, namely, t(1;2)(q25;p23), t(2;3)(p23;q21), t(2;17)(p23;q23) and inv(2)(p23q35), which create the TPM3-ALK, TFG-ALK5, CLTC-ALK, and ATIC-ALK fusion genes, respectively. Although overexpression of NPM-ALK has previously been shown to transform fibroblasts, the transforming potential of variant X-ALK proteins has not been precisely investigated. We stably transfected the cDNAs coding for NPM-ALK, TPM3-ALK, TFG-ALK, CLTC-ALK or ATIC-ALK into nonmalignant NIH3T3 cells. All X-ALK variants are tyrosine phosphorylated and their subcellular distribution was in agreement with that observed in tumors. Moreover, our results show that the in vitro transforming capacity of NIH3T3-transfected cells are in relation to the level of X-ALK fusion proteins excepted for TPM3-ALK for which there is an inverse correlation. The differences between the five X-ALK variants with regard to proliferation rate, colony formation in soft agar, invasion, migration through the endothelial barrier and tumorigenicity seem to be due to differential activation of various signaling pathways such as PI3-kinase/AKT. These findings may have clinical implications in the pathogenesis and prognosis of ALK-positive ALCLs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaplastic Lymphoma Kinase
  • Animals
  • Cell Division
  • Cell Line
  • Cell Line, Transformed
  • Cell Movement
  • Cell Transformation, Neoplastic*
  • Humans
  • Mice
  • Mice, Nude
  • NIH 3T3 Cells
  • Neoplasm Invasiveness
  • Neoplasms, Experimental / pathology
  • Protein-Tyrosine Kinases / genetics*
  • Receptor Protein-Tyrosine Kinases
  • Recombinant Fusion Proteins / analysis
  • Recombinant Fusion Proteins / genetics
  • Signal Transduction
  • Transfection

Substances

  • Recombinant Fusion Proteins
  • ALK protein, human
  • Alk protein, mouse
  • Anaplastic Lymphoma Kinase
  • Protein-Tyrosine Kinases
  • Receptor Protein-Tyrosine Kinases