title: Illegitimate WNT pathway activation by beta-catenin mutation or autocrine stimulation in T-cell malignancies.
abstract: Recent 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.
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Richard W J
authors.initials: RW
authors.lastname: Groen
authors.forename: Monique E C M
authors.initials: ME
authors.lastname: Oud
authors.forename: Esther J M
authors.initials: EJ
authors.lastname: Schilder-Tol
authors.forename: Marije B
authors.initials: MB
authors.lastname: Overdijk
authors.forename: Derk
authors.initials: D
authors.lastname: ten Berge
authors.forename: Roel
authors.initials: R
authors.lastname: Nusse
authors.forename: Marcel
authors.initials: M
authors.lastname: Spaargaren
authors.forename: Steven T
authors.initials: ST
authors.lastname: Pals