Selective ablation of the YxxM motif of IL-7Rα suppresses lymphomagenesis but maintains lymphocyte development

Tumor progression is a multiple step process in which, in addition to oncogenic mutation, other supporting factors can contribute to transformation. The role these factors have in cancer is an open question. Using the E mu-myc model of B-cell transformation, we evaluated the contribution of the cytokine interleukin-7 (IL-7) in supporting lymphomagenesis. We have previously shown that disruption of the Y449xxM motif of the IL-7 receptor alpha (IL-7R alpha) in a knock-in mouse model (IL-7R alpha(449F)) has minor effects on lymphocyte production, but interferes with the activation of survival effectors. To address the hypothesis that targeted signal ablation would selectively affect lymphocyte transformation, IL-7R alpha(449F) mice were crossed with two lymphomagenesis models, transgenic (Tg) IL-7 and E mu-myc mice. We found that the loss of IL-7R alpha Y449 signaling prevented Tg IL-7-mediated T-and B-lymphocyte transformation and decreased the development of E mu-myc-induced B-cell tumors. We showed that the IL-7R alpha(449F) mutation prevented increased survival of Tg IL-7 CD8 T cells, and decreased viability of bone marrow progenitor B cells, as well as E mu-myc-induced proliferation. This study shows that IL-7R alpha Y449 is important for lymphocyte transformation, and that unlike deficiencies in pre-B cell receptor signaling, Myc overexpression cannot compensate for the loss of IL-7R alpha signals in early B-cell development. Oncogene (2010) 29, 3854-3864; doi: 10.1038/onc.2010.133; published online 3 May 2010