Research ArticleCancer

FOXP1 potentiates Wnt/β-catenin signaling in diffuse large B cell lymphoma

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Science Signaling  03 Feb 2015:
Vol. 8, Issue 362, pp. ra12
DOI: 10.1126/scisignal.2005654

Targeting Wnt signaling in lymphoma

Although several human cancers show increased activity of the Wnt/β-catenin signaling pathway, tumors may lack mutations in components in this pathway that would account for the increase in activity. Using a gain-of-function screen and various cancer cell lines and in vivo models, Walker et al. found that the transcription factor FOXP1 (forkhead box protein P1) enhanced the transcription of Wnt-regulated target genes by binding to and promoting the acetylation of β-catenin. Patients with diffuse large B cell lymphomas overexpressing FOXP1 have a poor prognosis, and diffuse large B cell lymphoma cells with high FOXP1 abundance were sensitive to Wnt inhibitors. Xenografted tumors in mice were smaller when they lacked FOXP1 or when Wnt signaling was blocked.


The transcription factor FOXP1 (forkhead box protein P1) is a master regulator of stem and progenitor cell biology. In diffuse large B cell lymphoma (DLBCL), copy number amplifications and chromosomal translocations result in overexpression of FOXP1. Increased abundance of FOXP1 in DLBCL is a predictor of poor prognosis and resistance to therapy. We developed a genome-wide, mass spectrometry–coupled, gain-of-function genetic screen, which revealed that FOXP1 potentiates β-catenin–dependent, Wnt-dependent gene expression. Gain- and loss-of-function studies in cell models and zebrafish confirmed that FOXP1 was a general and conserved enhancer of Wnt signaling. In a Wnt-dependent fashion, FOXP1 formed a complex with β-catenin, TCF7L2 (transcription factor 7-like 2), and the acetyltransferase CBP [CREB (adenosine 3′,5′-monophosphate response element–binding protein)–binding protein], and this complex bound the promoters of Wnt target genes. FOXP1 promoted the acetylation of β-catenin by CBP, and acetylation was required for FOXP1-mediated potentiation of β-catenin–dependent transcription. In DLBCL, we found that FOXP1 promoted sensitivity to Wnt pathway inhibitors, and knockdown of FOXP1 or blocking β-catenin transcriptional activity slowed xenograft tumor growth. These data connect excessive FOXP1 with β-catenin–dependent signal transduction and provide a molecular rationale for Wnt-directed therapy in DLBCL.

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