Molecular pathogenesis of diffuse large B-cell lymphoma

The hematopoietic oncoprotein FOXP1 promotes tumor cell survival in diffuse large B-cell lymphoma by repressing S1PR2 signaling

Aberrant expression of the oncogenic transcription factor FOXP1 is a common feature of diffuse large B-cell lymphoma (DLBCL). We have combined chromatin immunoprecipitation and gene expression profiling after FOXP1 depletion with functional screening to identify targets of FOXP1 contributing to tumor cell survival. We find that the sphingosine-1-phosphate receptor 2 (S1PR2) is repressed by FOXP1 in activated B-cell (ABC) and germinal center B-cell (GCB) DLBCL cell lines with aberrantly high FOXP1 levels; S1PR2 expression is further inversely correlated with FOXP1 expression in three patient cohorts. Ectopic expression of wild type S1PR2, but not of a point mutant incapable of activating downstream signaling pathways, induces apoptosis in DLBCL cells and restricts tumor growth in subcutaneous and orthotopic models of the disease. The pro-apoptotic effects of S1PR2 are phenocopied by ectopic expression of the small G-protein Ga13, but are independent of AKT signaling. We further show that low S1PR2 expression is a strong negative prognosticator of patient survival, alone and especially in combination with high FOXP1 expression. The S1PR2 locus has previously been demonstrated to be recurrently mutated in GCB DLBCL; the transcriptional silencing of S1PR2 by FOXP1 represents an alternative mechanism leading to inactivation of this important hematopoietic tumor suppressor (see schematic in Figure for details). Further reading: Flori et al., Blood 2016

Figure 3

Figure. FOXP1 represses S1PR2 expression and downstream signaling pathways to promote cell survival in DLBCL. Schematic showing the FOXP1/S1PR2-regulated signaling pathways in normal and malignant B-cells. Under physiological conditions, a gradient of S1P with highest concentrations outside the germinal center (GC) and at the GC boundary inhibits migration and survival of FOXP1lo S1PR2hi GC B cells through S1PR2-mediated inhibition of RhoA and AKT signaling. In FOXP1-overexpressing (generally ABC-type) DLBCL, the transcriptional repression of S1PR2 promotes cell survival. In FOXP1lo GCB DLBCL on the other hand, the S1PR2 genomic locus is often mutated in coding as well as non-coding regions, leading to functional inactivation of S1PR2. Ectopic restoration of S1PR2 levels in ABC-type as well as GCB-type DLBCL cell lines induces apoptosis in a Ga13-dependent manner.