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

Abstract

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.

MicroRNA-96-5p promotes proliferation, invasion and EMT of oral carcinoma cells by directly targeting FOXF2

“…Forkhead transcription factors are characterized by a winged helix DNA-binding domain and are essential for embryogenesis (Kaufmann and Knöchel, 1996). Some of them, such as FOXQ1, FOXQ3 and FOXO1, have been identified as regulating tumorigenesis and tumor progression (Mottok et al, 2018;Saito et al, 2016;Chae et al, 2019). It has been reported that the Forkhead box F2 transcription factor (FOXF2) functions as tumor suppressor in breast cancer, gastric cancer, colorectal cancer, lung cancer and hepatocellular carcinoma (Cai et al, 2015;Higashimori et al, 2018;Zhang et al, 2015;Kundu et al, 2016;Shi et al, 2016).…”

Novel markers in pediatric-type follicular lymphoma

“…The FOXP-1 expression in PTFL was also confirmed at the RNA level by RNAscope in 5 cases (unpublished data). The level of FOXP-1 positivity in PTFL was higher than the one observed by Mottok et al [35] in conventional FL: they reported 40% of FOXP-1 + cases, applying a cutoff positivity of 10%. This discrepancy could be related to differences in sensitivity in the detection systems used in the two studies or might reflect the biological differences between PTFL and FL in adults as previously delineated by Schmidt at al.…”

“…FOXP-1 overexpression has been reported in association with t(3;14)(p14.1;q32), leading to a FOXP-1 -IGH fusion and in rearrangements with non-IG partners, causing the expression of the N-truncated isoforms, or in trisomy 3 [25–34]. Recently, Mottok et al [35] demonstrated that immunohistochemical expression of FOXP-1 predicted adverse failure–free survival in conventional FL treated with immunochemotherapy. They found FOXP-1 to be significantly downregulated in both EZH2 - and MEF2B -mutated cases and that high FOXP-1 expression was associated with distinct molecular features such as TP53 mutations, expression of IRF4, and gene expression signatures reminiscent of dark zone germinal center or activated B cells [35].…”

CRISPR/Cas9-Mediated Foxp1 Silencing Restores Immune Surveillance in an Immunocompetent A20 Lymphoma Model

“…This model thus provides a system in which to study the interplay between a B-cell lymphoma and its immune microenvironment. Importantly, FOXP1 is a marker of adverse outcome in other B-cell malignancies, including marginal zone lymphoma (25), chronic lymphocytic leukemia (26), and follicular lymphoma (27,28), Foxp1 expression patterns (both full length protein and smaller isoforms) and its repression of MHC-II, previously observed in human ABC-DLBCL (9), are both conserved in the murine A20 model. The current study also demonstrates that transient Foxp1 silencing in the A20 cell line did not compromise cell viability.…”