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

Richard W J Groen, Monique E C M Oud, Esther J M Schilder-Tol, Marije B Overdijk, Derk ten Berge, Roel Nusse, Marcel Spaargaren, Steven T Pals

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)6969-77
Number of pages9
JournalCancer Research
Volume68
Issue number17
DOIs
Publication statusPublished - 1 Sep 2008

Cite this

Groen, R. W. J., Oud, M. E. C. M., Schilder-Tol, E. J. M., Overdijk, M. B., ten Berge, D., Nusse, R., ... Pals, S. T. (2008). Illegitimate WNT pathway activation by beta-catenin mutation or autocrine stimulation in T-cell malignancies. Cancer Research, 68(17), 6969-77. https://doi.org/10.1158/0008-5472.CAN-08-1322