Submitted April 14, 2006
Accepted June 14, 2006
Loss of SHP1 enhances JAK3/STAT3 signaling and decreases
proteosome degradation of JAK3 and NPM-ALK in ALK-positive
anaplastic large-cell lymphoma
Yajun Han, Hesham Amin, Bevin Franko, Christine Frantz, Xinzhe Shi, and Raymond Lai*
Department of Laboratory Medicine and Pathology, U of Alberta
Department of Hematopathology, MD Anderson Cancer Center
* Corresponding author; email: raymondmail_65{at}yahoo.com.
Previous studies showed that most cases of ALK-positive
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 biological significance
of loss of SHP1 in ALK+ALCL, we transfected SHP1
plasmids into two SHP1-negative, 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 downregulation of STAT3 downstream
targets including cyclin D3, mcl-1 and bcl-2. Expression
of SHP1 in these two 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-positive ALK+ALCL cell line) was inhibited using
siRNA, pSTAT3, pJAK3, JAK3 and NPM-ALK were all
upregulated. Co-immunoprecipitation 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 two mechanisms: 1) leaves the tyrosine
phosphorylation and activation of JAK3/STAT3 unchecked,
and 2) decreases proteosome degradation of JAK3 and NPM-
ALK.
