Lymphocyte homeostasis is exquisitely sensitive to the cytokine interleukin (IL)-7. Loss of IL-7 signaling prevents lymphocyte development whereas excess IL-7 causes murine lymphoma and has been detected in several human lymphomas. We have previously shown that targeted disruption of the Y449xxM motif of the IL-7 receptor alpha (IL-7Rα) in a knock-in mouse model (IL-7Rα449F) has minor effects on lymphocyte production, but interferes with activation of survival effectors. We hypothesized that targeted signal ablation would selectively affect lymphocyte transformation. To address this, IL-7Rα449F mice were crossed with two lymphomagenesis models, transgenic (Tg) IL-7 and Eμ Myc mice. We found that loss of IL-7Rα Y449 signaling was sufficient to reverse the developmental aberrations induced by both the IL-7 and Eμ Myc transgenes, prevented Tg IL-7 mediated T and B lymphocyte transformation and significantly decreased development of Eμ Myc-induced B cell tumors. We show that the IL-7Rα449F mutation is essential for Tg IL-7 mediated up-regulation of pro-survival Bcl-2 family members, and for rapid cycling of bone marrow progenitor B cells induced by Eμ Myc. This study highlights the therapeutic potential of targeting the IL-7Rα Y449xxM motif or its downstream effectors in treatment of human lymphocyte malignancies.

Research supported by the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada and the Michael Smith Foundation for Health Research.