The molecular basis by which mutations in some ribosomal proteins (RP) predispose to development of hematologic malignancies remains unclear. We show here that germline inactivation of the ribosomal protein L22 (Rpl22), which selectively blocks T cell development, also predisposes T lineage progenitors to transformation. Indeed, RPL22 was found to be inactivated in ∼9% of human T-acute lymphoblastic leukemias (T-ALL). Moreover, mono-allelic loss of Rpl22 accelerates development of thymic lymphoma in a mouse model of T cell malignancy and in acute transformation assays in vitro. Furthermore, we show that Rpl22 inactivation enhances transformation potential through induction of Lin28B. These findings represent the first mechanistic insight into how an RP mutation promotes transformation.Our finding that Rpl22 inactivation promotes transformation by inducing expression of Lin28B provides insight into the mechanistic basis by which mutations in Rpl22, and perhaps other RP genes, increase cancer risk. In addition, because we have determined that Lin28B induction is dependent upon NF-kB activity, our findings may provide new opportunities for therapeutic intervention both in aggressive forms of T-ALL, where we have found Rpl22 to be inactivated, and perhaps in other diseases caused by mutations in RP genes.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1353. doi:1538-7445.AM2012-1353