title: Ribosomal Protein Rpl22 Controls the Dissemination of T-cell Lymphoma.
abstract: Mutations in ribosomal proteins cause bone marrow failure syndromes associated with increased cancer risk, but the basis by which they do so remains unclear. We reported previously that the ribosomal protein Rpl22 is a tumor suppressor in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL), and that loss of just one Rpl22 allele accelerates T-cell lymphomagenesis by activating NF-κB and inducing the stem cell factor Lin28B. Here, we show that, paradoxically, loss of both alleles of Rpl22 restricts lymphoma progression through a distinct effect on migration of malignant cells out of the thymus. Lymphoma-prone AKT2-transgenic or PTEN-deficient mice on an Rpl22(-/-) background developed significantly larger and markedly more vascularized thymic tumors than those observed in Rpl22(+/+) control mice. But, unlike Rpl22(+/+) or Rpl22(+/-) tumors, Rpl22(-/-) lymphomas did not disseminate to the periphery and were retained in the thymus. We traced the defect in the Rpl22(-/-) lymphoma migratory capacity to downregulation of the KLF2 transcription factor and its targets, including the key migratory factor sphingosine 1-phosphate receptor 1 (S1PR1). Indeed, reexpression of S1PR1 in Rpl22-deficient tumor cells restores their migratory capacity in vitro The regulation of KLF2 and S1PR1 by Rpl22 appears to be proximal as Rpl22 reexpression in Rpl22-deficient lymphoma cells restores expression of KLF2 and S1P1R, while Rpl22 knockdown in Rpl22-sufficient lymphomas attenuates their expression. Collectively, these data reveal that, while loss of one copy of Rpl22 promotes lymphomagenesis and disseminated disease, loss of both copies impairs responsiveness to migratory cues and restricts malignant cells to the thymus. Cancer Res; 76(11); 3387-96. ©2016 AACR.
authors.affiliation: Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Shuyun
authors.initials: S
authors.lastname: Rao
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Kathy Q
authors.initials: KQ
authors.lastname: Cai
authors.affiliation: Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Stadanlick
authors.affiliation: Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Noa
authors.initials: N
authors.lastname: Greenberg-Kushnir
authors.affiliation: Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Nehal
authors.initials: N
authors.lastname: Solanki-Patel
authors.affiliation: Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Sang-Yun
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Fahl
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Testa
authors.affiliation: Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania. david.wiest@fccc.edu.
authors.forename: David L
authors.initials: DL
authors.lastname: Wiest
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012269:Ribosomal Proteins / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D013953:Thymus Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D016328:NF-kappa B; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C522051:RPL22 protein, mouse; D012269:Ribosomal Proteins; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse