Selective ablation of the YxxM motif of IL-7Ralpha 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 Emicro-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-7Ralpha) in a knock-in mouse model (IL-7Ralpha(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-7Ralpha(449F) mice were crossed with two lymphomagenesis models, transgenic (Tg) IL-7 and Emicro-myc mice. We found that the loss of IL-7Ralpha Y449 signaling prevented Tg IL-7-mediated T- and B-lymphocyte transformation and decreased the development of Emicro-myc-induced B-cell tumors. We showed that the IL-7Ralpha(449F) mutation prevented increased survival of Tg IL-7 CD8 T cells, and decreased viability of bone marrow progenitor B cells, as well as Emicro-myc-induced proliferation. This study shows that IL-7Ralpha 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-7Ralpha signals in early B-cell development.