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

Lili Wang, Alex K. Shalek, Mike Lawrence, Ruihua Ding, Jellert T. Gaublomme, Nathalie Pochet, Petar Stojanov, Carrie Sougnez, Sachet A. Shukla, Kristen E. Stevenson, Wandi Zhang, Jessica Wong, Quinlan L. Sievers, Bryan T. MacDonald, Alexander R. Vartanov, Natalie R. Goldstein, Donna Neuberg, Xi He, Eric Lander, Nir HacohenAviv Regev, Gad Getz, Jennifer R. Brown, Hongkun Park, Catherine J. Wu

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1089-1098
Number of pages10
JournalBlood
Volume124
Issue number7
DOIs
StatePublished - Aug 14 2014
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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