FOXP1 expression is a prognostic biomarker in follicular lymphoma treated with rituximab and chemotherapy.

Follicular lymphoma (FL) is a clinically and molecularly highly heterogeneous disease, yet prognostication relies predominantly on clinical tools. We recently demonstrated that integration of mutation status of 7 genes, including and improves risk stratification. We mined gene expression data to uncover genes that are differentially expressed in - and -mutated cases. We focused on and assessed its protein expression by immunohistochemistry (IHC) in 763 tissue biopsies. For outcome correlation, a population-based training cohort of 142 patients with FL treated with rituximab, cyclophosphamide, vincristine, and prednisone, and a clinical trial validation cohort comprising 395 patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) ± rituximab were used. We found FOXP1 to be significantly downregulated in both - and -mutated cases. By IHC, 76 specimens in the training cohort (54%) had high FOXP1 expression (>10%), which was associated with reduced 5-year failure-free survival (FFS) rates (55% vs 70%). In the validation cohort, high FOXP1 expression status was observed in 248 patients (63%) and correlated with significantly shorter FFS in patients treated with R-CHOP (hazard ratio [HR], 1.95; = .017) but not in patients treated with CHOP (HR, 1.15; = .44). The impact of high FOXP1 expression on FFS in immunochemotherapy-treated patients was additional to the Follicular Lymphoma International Prognostic Index. High FOXP1 expression was associated with distinct molecular features such as mutations, expression of IRF4, and gene expression signatures reminiscent of dark zone germinal center or activated B cells. In summary, FOXP1 is a downstream phenotypic commonality of gene mutations and predicts outcome following rituximab-containing regimens.