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
Groen, Richard W J ; Oud, Monique E C M ; Schilder-Tol, Esther J M ; Overdijk, Marije B ; ten Berge, Derk ; Nusse, Roel ; Spaargaren, Marcel ; Pals, Steven T. / Illegitimate WNT pathway activation by beta-catenin mutation or autocrine stimulation in T-cell malignancies. In: Cancer Research. 2008 ; Vol. 68, No. 17. pp. 6969-77.
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Groen, RWJ, Oud, MECM, Schilder-Tol, EJM, Overdijk, MB, ten Berge, D, Nusse, R, Spaargaren, M & Pals, ST 2008, 'Illegitimate WNT pathway activation by beta-catenin mutation or autocrine stimulation in T-cell malignancies' Cancer Research, vol. 68, no. 17, pp. 6969-77. https://doi.org/10.1158/0008-5472.CAN-08-1322

Illegitimate WNT pathway activation by beta-catenin mutation or autocrine stimulation in T-cell malignancies. / Groen, Richard W J; Oud, Monique E C M; Schilder-Tol, Esther J M; Overdijk, Marije B; ten Berge, Derk; Nusse, Roel; Spaargaren, Marcel; Pals, Steven T.

In: Cancer Research, Vol. 68, No. 17, 01.09.2008, p. 6969-77.

Research output: Contribution to journalArticleAcademicpeer-review

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AU - Oud, Monique E C M

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AU - ten Berge, Derk

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AU - Spaargaren, Marcel

AU - Pals, Steven T

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AB - 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.

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KW - Mutation

KW - RNA, Messenger/genetics

KW - Signal Transduction

KW - Wnt Proteins/metabolism

KW - beta Catenin/genetics

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