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

Blood
Authors
Keywords
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.

Year of Publication
2014
Journal
Blood
Volume
124
Issue
7
Pages
1089-98
Date Published
2014 Aug 14
ISSN
1528-0020
URL
DOI
10.1182/blood-2014-01-552067
PubMed ID
24778153
PubMed Central ID
PMC4133483
Links
Grant list
R01 CA182461 / CA / NCI NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
5DP1OD003893-03 / OD / NIH HHS / United States
P30 CA014051 / CA / NCI NIH HHS / United States
K23 CA115682 / CA / NCI NIH HHS / United States
P50 HG006193 / HG / NHGRI NIH HHS / United States
Howard Hughes Medical Institute / United States
DP1 OD003893 / OD / NIH HHS / United States
1P50HG006193-01 / HG / NHGRI NIH HHS / United States