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.