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Rao S , Lee SY , Gutierrez A , Perrigoue J , Thapa RJ , Tu Z , Jeffers JR , Rhodes M , Anderson S , Oravecz T , Hunger SP , Timakhov RA , Zhang R , Balachandran S , Zambetti GP , Testa JR , Look AT , Wiest DL
Inactivation of ribosomal protein L22 promotes transformation by induction of the stemness factor, Lin28B
Blood. 2012 Nov 1;120(18) :3764-73
PMID: 22976955    PMCID: PMC3488889    URL: https://www.ncbi.nlm.nih.gov/pubmed/22976955
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Ribosomal protein (RP) mutations in diseases such as 5q- syndrome both disrupt hematopoiesis and increase the risk of developing hematologic malignancy. However, the mechanism by which RP mutations increase cancer risk has remained an important unanswered question. We show here that monoallelic, germline inactivation of the ribosomal protein L22 (Rpl22) predisposes T-lineage progenitors to transformation. Indeed, RPL22 was found to be inactivated in approximately 10% of human T-acute lymphoblastic leukemias. Moreover, monoallelic loss of Rpl22 accelerates development of thymic lymphoma in both a mouse model of T-cell malignancy and in acute transformation assays in vitro. We show that Rpl22 inactivation enhances transformation potential through induction of the stemness factor, Lin28B. Our finding that Rpl22 inactivation promotes transformation by inducing expression of Lin28B provides the first insight into the mechanistic basis by which mutations in Rpl22, and perhaps some other RP genes, increases cancer risk.
Rao, Shuyun Lee, Sang-Yun Gutierrez, Alejandro Perrigoue, Jacqueline Thapa, Roshan J Tu, Zhigang Jeffers, John R Rhodes, Michele Anderson, Stephen Oravecz, Tamas Hunger, Stephen P Timakhov, Roman A Zhang, Rugang Balachandran, Siddharth Zambetti, Gerard P Testa, Joseph R Look, A Thomas Wiest, David L eng 5P01CA068484/CA/NCI NIH HHS/ P01CA06927/CA/NCI NIH HHS/ R01 AI073920/AI/NIAID NIH HHS/ R01-AI073920/AI/NIAID NIH HHS/ R21-CA141194/CA/NCI NIH HHS/ R01 CA077429/CA/NCI NIH HHS/ P30 DK050306/DK/NIDDK NIH HHS/ P30-DK-50306/DK/NIDDK NIH HHS/ K08 CA133103/CA/NCI NIH HHS/ 5K08CA133103/CA/NCI NIH HHS/ R01-CA77429/CA/NCI NIH HHS/ R21 CA141194/CA/NCI NIH HHS/ P01 CA068484/CA/NCI NIH HHS/ P30 CA006927/CA/NCI NIH HHS/ U10 CA98543/CA/NCI NIH HHS/ T32 CA009035/CA/NCI NIH HHS/ U10 CA98413/CA/NCI NIH HHS/ CA009035/CA/NCI NIH HHS/ U10 CA098413/CA/NCI NIH HHS/ U24 CA114766/CA/NCI NIH HHS/ R01 CA160331/CA/NCI NIH HHS/ U10 CA098543/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Blood. 2012 Nov 1;120(18):3764-73. doi: 10.1182/blood-2012-03-415349. Epub 2012 Sep 13.