| |
|
|
|
|
|
|
|||
|
Blood, 15 October 2006, Vol. 108, No. 8, pp. 2796-2803. Prepublished online as a Blood First Edition Paper on July 6, 2006; DOI 10.1182/blood-2006-04-017434.
NEOPLASIA Loss of SHP1 enhances JAK3/STAT3 signaling and decreases proteosome degradation of JAK3 and NPM-ALK in ALK+ anaplastic large-cell lymphomaFrom the Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada; and Department of Hematopathology, the University of Texas M. D. Anderson Cancer Center, Houston.
Previous studies showed that most cases of ALK+ anaplastic large-cell lymphoma (ALK+ALCL) do not express SHP1, a tyrosine phosphatase and an important negative regulator for cellular signaling pathways such as that of JAK/STAT. To fully assess the biologic significance of loss of SHP1 in ALK+ALCL, we transfected SHP1 plasmids into 2 SHP1-, ALK+ALCL cell lines, Karpas 299 and SU-DHL-1. After 24 hours of transfection, pJAK3 and pSTAT3 were decreased, and these changes correlated with down-regulation of STAT3 downstream targets including cyclin D3, mcl-1, and bcl-2. Expression of SHP1 in these 2 cell lines also resulted in marked decreases in the protein levels of JAK3 and NPM-ALK, and these effects were reversible by proteosome inhibitor MG132. Conversely, when SHP1 expression in SUP-M2 (a SHP1+ ALK+ALCL cell line) was inhibited using siRNA, pSTAT3, pJAK3, JAK3, and NPM-ALK were all up-regulated. Coimmunoprecipitation studies showed that SHP1 was physically associated with JAK3 and NPM-ALK. SHP1 expression in Karpas 299 and SU-DHL-1 led to significant G1 cell cycle arrest but not apoptosis. To conclude, loss of SHP1 contributes to the pathogenesis of ALK+ALCL by 2 mechanisms: (1) it leaves the tyrosine phosphorylation and activation of JAK3/STAT3 unchecked and (2) it decreases proteosome degradation of JAK3 and NPM-ALK.
Related Article in Blood Online:
This article has been cited by other articles:
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Copyright © 2006 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||