Submitted September 20, 2007
Accepted February 26, 2008
Induction of the IL-9 gene by HTLV-I Tax stimulates the spontaneous proliferation of primary adult T-cell leukemia cells by a paracrine mechanism
Jing Chen, Mike Petrus, Bonita R Bryant, Vinh Phuc Nguyen, Mindy Stamer, Carolyn K Goldman, Richard Bamford, John C Morris, John E Janik, and Thomas A Waldmann*
Metabolism Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD
Transponics, Jacobus, PA
* Corresponding author; email: tawald{at}helix.nih.gov.
The etiological agent of adult T cell leukemia (ATL) is the retrovirus human T cell lymphotropic virus type I (HTLV-I). The HTLV-I protein Tax alters gene expression including those of cytokines and their receptors which plays an important role in the early stages of ATL. Here we demonstrate that expression of IL-9 is activated by Tax via an NF-
B motif in its proximal promoter while IL-9 receptor-
expression is not induced by Tax. However, supporting a role for IL-9/IL-9R in ATL, a neutralizing monoclonal antibody directed toward IL-9R[alpha] inhibited ex vivo spontaneous proliferation of primary ATL cells obtained from several patients. FACS analysis of freshly isolated PBMCs from these patients revealed high level expression of IL-9R on their CD14 expressing monocytes. Furthermore, purified T cells or monocytes alone from these patients did not proliferate ex vivo, whereas the mixture of these cell types manifested significant proliferation through a contact- dependent manner. Taken together, our data suggest that primary ATL cells, via IL-9, support the action of IL-9R/CD14 expressing monocytes, which subsequently support the ex vivo spontaneous proliferation of malignant T cells. In summary, these data support a role for IL-9 and its receptor in ATL by a paracrine mechanism.
