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Blood DOI:10.1182/blood-2014-01-552067

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

Publication TypeJournal Article
Year of Publication2014
AuthorsWang, L, Shalek, AK, Lawrence, M, Ding, R, Gaublomme, JT, Pochet, N, Stojanov, P, Sougnez, C, Shukla, SA, Stevenson, KE, Zhang, W, Wong, J, Sievers, QL, MacDonald, BT, Vartanov, AR, Goldstein, NR, Neuberg, D, He, X, Lander, E, Hacohen, N, Regev, A, Getz, G, Brown, JR, Park, H, Wu, CJ
Date Published2014 Aug 14
KeywordsAdult, beta Catenin, Cell Line, Tumor, Cell Survival, Cells, Cultured, Gene Expression Profiling, Gene Expression Regulation, Leukemic, HEK293 Cells, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Mutation, Oligonucleotide Array Sequence Analysis, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, Signal Transduction, Wnt Signaling Pathway

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.


Alternate JournalBlood
PubMed ID24778153
PubMed Central IDPMC4133483
Grant ListR01 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