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Rao SY , Lee SY , Gutierrez A , Perrigoue J , Thapa RJ , Tu ZG , Jeffers JR , Rhodes M , Anderson S , Oravecz T , Hunger SP , Timakhov RA , Zhang RG , 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;120(18) :3764-3773
PMID: WOS:000311624800020    PMCID: PMC3488889   
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Abstract
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 similar to 10% of human T-acute lymphoblastic lweukemias. 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. (Blood.2012;120(18):3764-3773)
Notes
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. National Institutes of Health [R01-AI073920, R01-CA77429, R21-CA141194, P01CA06927, T32 CA009035, 5K08CA133103]; Center grant [P30-DK-50306]; Commonwealth of Pennsylvania; Blood Cell Development and Cancer Keystone; Greenwald and Plain & Fancy Fellowships; American Society of Hematology-Amos Faculty Development Program; [U10 CA98543]; [U10 CA98413]; [U24 CA114766]; [5P01CA068484] This work was supported by National Institutes of Health grants R01-AI073920, R01-CA77429, and R21-CA141194; National Institutes of Health core grant P01CA06927; Center grant P30-DK-50306; an appropriation from the Commonwealth of Pennsylvania; and support from the Blood Cell Development and Cancer Keystone. This work was supported in part by grants to the COG, including U10 CA98543 (COG Chair's grant), U10 CA98413 (COG Statistical Center), and U24 CA114766 (COG Specimen Banking), as well as by grant 5P01CA068484 (to the Dana-Farber Cancer Institute and A. T. L.). S.Y.L. was supported by both the Greenwald and Plain & Fancy Fellowships. J.P. is a Merck fellow of the Life Sciences Research Fellowship and was a fellow of the National Institutes of HealthT32 CA009035 training grant. A. G. is a scholar of the American Society of Hematology-Amos Faculty Development Program and is supported by National Institutes of Health grant 5K08CA133103. 50 Amer soc hematology Washington 044mw