Autocrine release of interleukin-9 promotes Jak3-dependent survival of ALK+ anaplastic large-cell lymphoma cells.
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 (gammac) 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-9Ralpha and IL-9 in 3 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 up-regulation of p21 and down-regulation 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 patients with ALK+ ALCL.
Qiu
Lin
L
Department of Hematopathology, Box 72, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
Lai
Raymond
R
Lin
Quan
Q
Lau
Esther
E
Thomazy
David M
DM
Calame
Daniel
D
Ford
Richard J
RJ
Kwak
Larry W
LW
Kirken
Robert A
RA
Amin
Hesham M
HM
D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology*; D002470:Cell Survival; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016906:Interleukin-9 / Q000378:metabolism / Q000502:physiology*; D053616:Janus Kinase 3; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases
D016906:Interleukin-9; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; C507933:JAK3 protein, human; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3