Illegitimate WNT pathway activation by beta-catenin mutation or autocrine stimulation in T-cell malignancies.

TitleIllegitimate WNT pathway activation by beta-catenin mutation or autocrine stimulation in T-cell malignancies.
Publication TypeJournal Article
Year of Publication2008
AuthorsGroen RWJ, Oud MECM, Schilder-Tol EJM, Overdijk MB, ten Berge D, Nusse R, Spaargaren M, Pals ST
JournalCancer Res
Volume68
Pagination6969–6977
Date PublishedSep
ISSN1538-7445 (Electronic); 0008-5472 (Linking)
AbstractRecent studies in mice have shown a role for the canonical WNT pathway in lymphocyte development. Because cancers often arise as a result of aberrant activation of signaling cascades that normally promote the self-renewal and expansion of their progenitor cells, we hypothesized that activation of the WNT pathway might contribute to the pathogenesis of lymphoproliferative disease. Therefore, we screened a large panel (n = 162) of non-Hodgkin lymphomas (NHL), including all major WHO categories, for nuclear expression of beta-catenin, a hallmark of "active" WNT signaling. In 16 lymphomas, mostly of T-lineage origin, nuclear localization of beta-catenin was detected. Interestingly, some of these tumors contained established gain-of-function mutations in the gene encoding beta-catenin (CTNNB1); however, in the majority, mutations in either CTNNB1 or APC were not detected. Functional analysis of WNT signaling in precursor T-lymphoblastic lymphomas/leukemias, the NHL subset in which beta-catenin accumulation was most prevalent (33% positive), revealed a constitutively activated, but still responsive, WNT pathway, which controlled T-cell factor-mediated gene transcription and cell growth. Our data indicate that activation of the WNT pathway, either by CTNNB1 mutation or autocrine stimulation, plays a role in the pathogenesis of a subset of NHLs, in particular, those of T-cell origin.
DOI10.1158/0008-5472.CAN-08-1322