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

Somatic mutation as a mechanism of Wnt/β-catenin pathway activation in CLL

  1. Lili Wang1,2,
  2. Alex K. Shalek3,
  3. Mike Lawrence4,
  4. Ruihua Ding3,
  5. Jellert T. Gaublomme3,
  6. Nathalie Pochet4,
  7. Petar Stojanov4,
  8. Carrie Sougnez4,
  9. Sachet A. Shukla1,2,
  10. Kristen E. Stevenson5,
  11. Wandi Zhang1,2,
  12. Jessica Wong1,2,
  13. Quinlan L. Sievers1,2,
  14. Bryan T. MacDonald6,7,
  15. Alexander R. Vartanov2,
  16. Natalie R. Goldstein2,
  17. Donna Neuberg5,
  18. Xi He6,7,
  19. Eric Lander4,
  20. Nir Hacohen4,8,
  21. Aviv Regev4,
  22. Gad Getz4,
  23. Jennifer R. Brown2,9,
  24. Hongkun Park3, and
  25. Catherine J. Wu1,2,9
  1. 1Cancer Vaccine Center, and
  2. 2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
  3. 3Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA;
  4. 4Broad Institute, Cambridge, MA;
  5. 5Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA;
  6. 6F. M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA;
  7. 7Department of Neurology, Harvard Medical School, Boston, MA;
  8. 8Division of Allergy, Immunology and Rheumatology, Department of Medicine, Massachusetts General Hospital, Boston MA; and
  9. 9Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA

Key Points

  • Wnt pathway is frequently mutated in CLL.

  • Wnt pathway mutations can lead to pathway activation and enhanced CLL survival.

Abstract

One major goal of cancer genome sequencing is to identify key genes and pathways that drive tumor pathogenesis. Although many studies have identified candidate driver genes based on recurrence of mutations in individual genes, subsets of genes with nonrecurrent mutations may also be defined as putative drivers if they affect a single biological pathway. In this fashion, we previously identified Wnt signaling as significantly mutated through large-scale massively parallel DNA sequencing of chronic lymphocytic leukemia (CLL). Here, we use a novel method of biomolecule delivery, vertical silicon nanowires, to efficiently introduce small interfering RNAs into CLL cells, and interrogate the effects of 8 of 15 mutated Wnt pathway members identified across 91 CLLs. In HEK293T cells, mutations in 2 genes did not generate functional changes, 3 led to dysregulated pathway activation, and 3 led to further activation or loss of repression of pathway activation. Silencing 4 of 8 mutated genes in CLL samples harboring the mutated alleles resulted in reduced viability compared with leukemia samples with wild-type alleles. We demonstrate that somatic mutations in CLL can generate dependence on this pathway for survival. These findings support the notion that nonrecurrent mutations at different nodes of the Wnt pathway can contribute to leukemogenesis.

  • Submitted January 28, 2014.
  • Accepted April 10, 2014.
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