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Illegitimate WNT Pathway Activation by β-Catenin Mutation or Autocrine Stimulation in T-Cell Malignancies

¹ Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands and ² Howard Hughes Medical Institute and Department of Developmental Biology, Stanford University, Stanford, California

Requests for reprints: Steven T. Pals, Department of Pathology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands. Phone: 31-20-5665644; Fax: 31-20-5669523; E-mail: s.t.pals{at}amc.uva.nl.

Key Words: β-catenin • WNT • non–Hodgkin lymphoma • ALL • NOTCH

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 β-catenin, a hallmark of "active" WNT signaling. In 16 lymphomas, mostly of T-lineage origin, nuclear localization of β-catenin was detected. Interestingly, some of these tumors contained established gain-of-function mutations in the gene encoding β-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 β-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. [Cancer Res 2008;68(17):6969–77]

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