Blood Journal
Leading the way in experimental and clinical research in hematology

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

  1. Shuyun Rao1,2,*,
  2. Sang-Yun Lee1,2,*,
  3. Alejandro Gutierrez3,
  4. Jacqueline Perrigoue1,2,
  5. Roshan J. Thapa2,
  6. Zhigang Tu4,
  7. John R. Jeffers5,
  8. Michele Rhodes1,2,
  9. Stephen Anderson6,
  10. Tamas Oravecz6,
  11. Stephen P. Hunger7,
  12. Roman A. Timakhov8,
  13. Rugang Zhang4,
  14. Siddharth Balachandran2,
  15. Gerard P. Zambetti5,
  16. Joseph R. Testa1,8,
  17. A. Thomas Look3, and
  18. David L. Wiest1,2
  1. 1Blood Cell Development and Cancer Keystone, and
  2. 2Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, Philadelphia, PA;
  3. 3Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital Boston, Boston, MA;
  4. 4Women's Cancer Program, Fox Chase Cancer Center, Philadelphia, PA;
  5. 5Department of Biochemistry, St Jude Children's Research Hospital, Memphis, TN;
  6. 6Department of Immunology, Lexicon Pharmaceuticals Inc, The Woodlands, TX;
  7. 7Section of Pediatric Hematology/Oncology/Bone Marrow Transplantation, University of Colorado Denver School of Medicine, Aurora, CO; and
  8. 8Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA

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.

  • Submitted March 3, 2012.
  • Accepted September 2, 2012.
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