Novel Role for Rpl22 in Controlling Lymphoma Progression and Dissemination

Mutations in ribosomal proteins often cause bone marrow failure syndromes associated with increased risk for cancer development; however, in most cases, the basis by which they do so remains unclear. We have shown that Rpl22 is a haploinsufficient tumor suppressor in T acute lymphoblastic leukemia/lymphoma (T-ALL). Loss one Rpl22 allele accelerates T-cell lymphomagenesis in the murine Akt transgenic mouse model, by inducing the stem cell factor Lin28B in an NFkB-dependent manner. Here we employed two distinct murine T lymphoma models to uncover a new role for Rpl22 in lymphoma progression through effects on migration and angiogenesis. Compared with Rpl22+/+ mice, mice deficient for Rpl22 (Rpl22-/-) exhibited significantly increased thymic tumor size, which was associated with markedly enhanced angiogenesis through the activation of VEGF signaling. Unlike Rpl22 sufficient tumors, Rpl22-deficient lymphomas were retained in the thymus as a large mediastinal mass that did not disseminate to the periphery due to a defect in migration. The migration defect in Rpl22-/- tumors results from attenuation of S1P1 receptor expression through downregulation of the KLF2 transcriptional factor, which is responsible for its expression. Indeed, re-expression of S1P1 receptor in Rpl22 deficient tumor cells rescues the migration defect. Re-expression of Rpl22 into Rpl22 deficient cells rescues expression of both KLF2 and its target, S1P1 receptor, indicating that Rpl22 is regulating the KLF2/S1P1 receptor axis, rather than the changes in expression being an indirect consequence of transformation. Consistent with this idea, human T-ALL lines with in which Rpl22 is mutated, exhibit reduced expression of both KLF2 and S1P1 receptor, relative to that in T-ALL lines with intact RPL22 alleles. Collectively, we have defined a new role of Rpl22 in tumorigenesis through regulation of migration.