Inactivation of ribosomal protein L22 promotes transformation by induction of the stemness factor, Lin28B

Author:

Rao Shuyun12,Lee Sang-Yun12,Gutierrez Alejandro3,Perrigoue Jacqueline12,Thapa Roshan J.2,Tu Zhigang4,Jeffers John R.5,Rhodes Michele12,Anderson Stephen6,Oravecz Tamas6,Hunger Stephen P.7,Timakhov Roman A.8,Zhang Rugang4,Balachandran Siddharth2,Zambetti Gerard P.5,Testa Joseph R.18,Look A. Thomas3,Wiest David L.12

Affiliation:

1. Blood Cell Development and Cancer Keystone, and

2. Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, Philadelphia, PA;

3. Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital Boston, Boston, MA;

4. Women's Cancer Program, Fox Chase Cancer Center, Philadelphia, PA;

5. Department of Biochemistry, St Jude Children's Research Hospital, Memphis, TN;

6. Department of Immunology, Lexicon Pharmaceuticals Inc, The Woodlands, TX;

7. Section of Pediatric Hematology/Oncology/Bone Marrow Transplantation, University of Colorado Denver School of Medicine, Aurora, CO; and

8. Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA

Abstract

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 ∼ 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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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