Submitted April 27, 2006
Accepted May 27, 2006
Autocrine Release of Interleukin-9 Promotes Jak3-Dependent Survival of ALK+ Anaplastic Large Cell
Lymphoma Cells
Lin Qiu, Raymond Lai, Quan Lin, Esther Lau, David M. Thomazy, Daniel Calame, Richard J. Ford, Larry W. Kwak, Robert A. Kirken, and Hesham M. Amin*
Hematopathology, M. D. Anderson Cancer Center
The University of Alberta and Cross Cancer Institute
M. D. Anderson Cancer Center
The University of Texas at El-Paso
* Corresponding author; email: hamin{at}mdanderson.org.
The aberrant fusion protein NPM-ALK plays an important
pathogenetic role in ALK+ anaplastic large cell lymphoma
(ALCL). We previously demonstrated that Jak3 potentiates
the activity of NPM-ALK. Jak3 activation is restricted
to interleukins that recruit the common gamma chain (
c)
receptor, including IL-9. NPM-ALK was previously shown
to promote widespread lymphomas in IL-9 transgenic mice
by unknown mechanisms. We hypothesized that IL-9 plays
an important role in ALK+ ALCL via Jak3 activation. Our
studies demonstrate the expression of IL-9R
and IL-9 in
three ALK+ ALCL cell lines and 75% and 83% of primary
tumors, respectively. IL-9 was detected in serum-free
culture medium harvested from ALK+ ALCL cell lines,
supporting autocrine release of IL-9. Treatment of these
cells with an anti-IL-9 neutralizing antibody decreased
pJak3 and its kinase activity, along with pStat3 and
ALK kinase activity. These effects were associated with decreased cell
proliferation and colony formation in soft agar and cell
cycle arrest. Evidence suggests that cell cycle arrest
can be attributed to upregulation of p21 and
downregulation of Pim-1. Our results illustrate that IL-
9/Jak3 signaling plays a significant role in the
pathogenesis of ALK+ ALCL, and that it represents a
potential therapeutic target for treating ALK+ ALCL
patients.
