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  1. Usman AN, Ahmad M, Sinrang AW, Natsir S, Takko AB, Ariyandy A, et al.
    Breast Dis, 2023;42(1):213-218.
    PMID: 37458005 DOI: 10.3233/BD-239002
    BACKGROUND: FOXP3 Tregs have been found in breast cancer patients, both humoral and tumor. Survival or prognosis of breast cancer patients seems to correlate with the increase and decrease in FOXP3 Treg.

    OBJECTIVES: This review aims to provide insights regarding the FOXP3 Tregs involved and their mechanisms in breast cancer prognosis.

    METHODS: The literature study method is used from primary and secondary libraries. The library search used online-based search instruments such as NCBI-PubMed, Google Scholar, and Elsevier. The data obtained were then arranged according to the framework, data on the relationship between FOXP3 Regulatory T Cells and breast cancer, and writing a journal review was carried out according to the given format. Regulators (Tregs) can inhibit anti-tumor immunity and promote tumor growth. Tregs also play a role in inhibiting cytotoxic T lymphocyte cells by inhibiting the release of granules from CD8+, where CD8+ is important in killing tumor cells. FOXP3 is a Treg-specific biomarker and plays an important role in the development and function of Tregs.

    RESULTS: Studies on the presence of FOXP3+ Tregs in tumors have shown controversial results. Studies in some tumors reported the presence of FOXP3+, indicating a poor prognosis, whereas studies in other tumors found that FOXP3+ correlated with a good prognosis.

    CONCLUSION: Regulatory T lymphocytes and TILs in invasive breast carcinoma are still not established. Therefore, further research on the Effect of FOXP3 expression of regulatory T lymphocytes on breast cancer is still important.

    Matched MeSH terms: Forkhead Transcription Factors/genetics; Forkhead Transcription Factors/metabolism
  2. Ma A, Yousoof S, Grigg JR, Flaherty M, Minoche AE, Cowley MJ, et al.
    Genet Med, 2020 10;22(10):1623-1632.
    PMID: 32499604 DOI: 10.1038/s41436-020-0854-x
    PURPOSE: Ocular anterior segment disorders (ASDs) are clinically and genetically heterogeneous, and genetic diagnosis often remains elusive. In this study, we demonstrate the value of a combined analysis protocol using phenotypic, genomic, and pedigree structure data to achieve a genetic conclusion.

    METHODS: We utilized a combination of chromosome microarray, exome sequencing, and genome sequencing with structural variant and trio analysis to investigate a cohort of 41 predominantly sporadic cases.

    RESULTS: We identified likely causative variants in 54% (22/41) of cases, including 51% (19/37) of sporadic cases and 75% (3/4) of cases initially referred as familial ASD. Two-thirds of sporadic cases were found to have heterozygous variants, which in most cases were de novo. Approximately one-third (7/22) of genetic diagnoses were found in rarely reported or recently identified ASD genes including PXDN, GJA8, COL4A1, ITPR1, CPAMD8, as well as the new phenotypic association of Axenfeld-Rieger anomaly with a homozygous ADAMTS17 variant. The remainder of the variants were in key ASD genes including FOXC1, PITX2, CYP1B1, FOXE3, and PAX6.

    CONCLUSIONS: We demonstrate the benefit of detailed phenotypic, genomic, variant, and segregation analysis to uncover some of the previously "hidden" heritable answers in several rarely reported and newly identified ocular ASD-related disease genes.

    Matched MeSH terms: Forkhead Transcription Factors/genetics
  3. Kalaw E, Lim M, Kutasovic JR, Sokolova A, Taege L, Johnstone K, et al.
    Br J Cancer, 2020 11;123(11):1665-1672.
    PMID: 32939056 DOI: 10.1038/s41416-020-01065-3
    BACKGROUND: Metaplastic breast carcinoma encompasses a heterogeneous group of tumours with differentiation into squamous and/or spindle, chondroid, osseous or rhabdoid mesenchymal-looking elements. Emerging immunotherapies targeting Programmed Death Ligand 1 (PD-L1) and immune-suppressing T cells (Tregs) may benefit metaplastic breast cancer patients, which are typically chemo-resistant and do not express hormone therapy targets.

    METHODS: We evaluated the immunohistochemical expression of PD-L1 and FOXP3, and the extent of tumour infiltrating lymphocytes (TILs) in a large cohort of metaplastic breast cancers, with survival data.

    RESULTS: Metaplastic breast cancers were significantly enriched for PD-L1 positive tumour cells, compared to triple-negative ductal breast cancers (P 

    Matched MeSH terms: Forkhead Transcription Factors/biosynthesis*
  4. Lee WQ, Leong KF
    Pediatr Dermatol, 2023;40(5):886-889.
    PMID: 36727435 DOI: 10.1111/pde.15266
    Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) is characterized by failure to thrive, severe chronic diarrhea, neonatal type 1 diabetes or thyroiditis, and eczematous dermatitis. We report a patient with infantile onset IPEX syndrome who developed vitiligo, alopecia, and chronic diarrhea. Awaiting stem cell transplant, he had multiple episodes of sepsis and succumbed at the age of 10 months. The constellation of symptoms is important to prompt clinicians to suspect this rare syndrome as early hematopoietic stem cell transplantation is the only cure for IPEX patients.
    Matched MeSH terms: Forkhead Transcription Factors/genetics
  5. Gazi U, Baykam N, Karasartova D, Tosun O, Akdogan O, Yapar D, et al.
    Trop Biomed, 2022 Dec 01;39(4):587-591.
    PMID: 36602220 DOI: 10.47665/tb.39.4.016
    Crimean-Congo haemorrhagic fever (CCHF) is a severe human infection which can lead to fatal consequences. Acute CCHF patients were previously shown to exhibit frequencies of regulatory T-cell (Treg) but lower Treg-mediated suppressive activities than the healthy counterparts. This study aims is to investigate the phosphorylation levels of Foxp3 protein (master regulator of Treg cells) in CCHF patients. Blood samples collected from 18 CCHF patients and nine healthy volunteers were used to isolate peripheral blood mononuclear cells (PBMCs). Total and phosphorylated Foxp3 expression levels in the isolated PBMC samples were monitored by western blot and quantified using ImageJ software. Total Foxp3 expression levels in CCHF patients displayed decreasing trend, but not significantly. In contrast, significantly lower expression levels of phosphorylated Foxp3 were reported in CCHF patients. Our results suggest a possible association between Foxp3 dephosphorylation and CCHF pathogenesis. Nevertheless, more studies are required to evaluate the effect of Foxp3 dephosphorylation on Treg function, which would not only help to enlighten the CCHF pathogenesis but also contribute to the development of effective treatment strategies.
    Matched MeSH terms: Forkhead Transcription Factors
  6. Yip WK, Leong VC, Abdullah MA, Yusoff S, Seow HF
    Oncol Rep, 2008 Feb;19(2):319-28.
    PMID: 18202777
    The Akt pathway is one of the most common molecular alterations in various human malignancies. However, its involvement in nasopharyngeal carcinoma (NPC) tumorigenesis has not been well established. In this study, the status of Akt activation and expression of its upstream and downstream molecules was investigated in 64 NPC and 38 non-malignant nasopharyngeal tissues by immunohistochemistry. The hotspot mutations of PIK3CA, encoding the p110alpha catalytic subunit of phosphatidylinositol 3-kinase (PI3K), were also determined in 25 of these NPC tissues. No hotspot mutations were found in any of the samples tested. Akt was activated in 27 (42.2%) and 23 (35.9%) NPCs, as indicated by p-Akt (Thr308) and p-Akt (Ser473) immunoreactivity, respectively. PTEN loss did not correlate statistically with activated Akt. However, a positive correlation was observed between activated Akt and phospho-epidermal growth factor receptor (p-EGFR), suggesting that the EGFR signaling might be one of the upstream regulators of the Akt pathway. The phosphorylation of forkhead (FKHR) and Bcl-2 associated death domain (BAD), but not mammalian target of rapamycin and glycogen synthase kinase-3beta, was significantly correlated with Akt activation. This implies that Akt promotes cell proliferation (as estimated by Ki-67) and survival, at least, through the inactivation of FKHR and BAD in NPC. Our data revealed that the EGFR/PI3K/Akt signaling pathway is important in NPC pathogenesis and that PIK3CA hotspot mutations are rare in NPC.
    Matched MeSH terms: Forkhead Transcription Factors/analysis; Forkhead Transcription Factors/metabolism*
  7. Poli A, Abdul-Hamid S, Zaurito AE, Campagnoli F, Bevilacqua V, Sheth B, et al.
    Proc Natl Acad Sci U S A, 2021 08 03;118(31).
    PMID: 34312224 DOI: 10.1073/pnas.2010053118
    Regulatory T cells (Tregs) play fundamental roles in maintaining peripheral tolerance to prevent autoimmunity and limit legitimate immune responses, a feature hijacked in tumor microenvironments in which the recruitment of Tregs often extinguishes immune surveillance through suppression of T-effector cell signaling and tumor cell killing. The pharmacological tuning of Treg activity without impacting on T conventional (Tconv) cell activity would likely be beneficial in the treatment of various human pathologies. PIP4K2A, 2B, and 2C constitute a family of lipid kinases that phosphorylate PtdIns5P to PtdIns(4,5)P 2 They are involved in stress signaling, act as synthetic lethal targets in p53-null tumors, and in mice, the loss of PIP4K2C leads to late onset hyperinflammation. Accordingly, a human single nucleotide polymorphism (SNP) near the PIP4K2C gene is linked with susceptibility to autoimmune diseases. How PIP4Ks impact on human T cell signaling is not known. Using ex vivo human primary T cells, we found that PIP4K activity is required for Treg cell signaling and immunosuppressive activity. Genetic and pharmacological inhibition of PIP4K in Tregs reduces signaling through the PI3K, mTORC1/S6, and MAPK pathways, impairs cell proliferation, and increases activation-induced cell death while sparing Tconv. PIP4K and PI3K signaling regulate the expression of the Treg master transcriptional activator FOXP3 and the epigenetic signaling protein Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1). Our studies suggest that the pharmacological inhibition of PIP4K can reprogram human Treg identity while leaving Tconv cell signaling and T-helper differentiation to largely intact potentially enhancing overall immunological activity.
    Matched MeSH terms: Forkhead Transcription Factors/genetics; Forkhead Transcription Factors/metabolism*
  8. Ismail IH, Boyle RJ, Mah LJ, Licciardi PV, Tang ML
    Pediatr Allergy Immunol, 2014 Nov;25(7):674-84.
    PMID: 25376403 DOI: 10.1111/pai.12303
    Regulatory T cells (Treg) play an essential role in early immune programming and shaping the immune response towards a pro-allergic or tolerant state. We evaluated cord blood Treg and cytokine responses to microbial and non-microbial stimuli in infants at high risk of allergic disease and their associations with development of allergic disease in the first year.
    Matched MeSH terms: Forkhead Transcription Factors/metabolism
  9. Azmahani A, Nakamura Y, Ozawa Y, McNamara KM, Fujimura T, Haga T, et al.
    Hum Pathol, 2015 Nov;46(11):1662-9.
    PMID: 26359540 DOI: 10.1016/j.humpath.2015.07.007
    Extramammary Paget disease (EMPD) has been known to frequently express androgen receptor (AR). Therefore, androgens could play roles in the biological behavior of Paget cells. 5α-Reductase (5α-red) types 1 and 2 and 17β-hydroxysteroid dehydrogenase type 5 (17β-HSD5) are pivotal in situ regulators of androgen production in androgen-responsive tissues including androgen-dependent neoplasms. Therefore, in this study, we immunolocalized AR, androgen-producing enzymes, and their transcription factors to assess the state of in situ androgen production and actions and its correlation of invasiveness in EMPD. We studied 51 cases of EMPD with known clinicopathological status. AR, 5α-red1, 17β-HSD5, and β-catenin immunoreactivity was evaluated by using the modified H-score method while cyclin D1, p53, forkhead box protein P1, and a proliferation marker, Ki-67, were quantified using labeling index. The mean scores of AR, 5α-red1, and 17β-HSD5 in invasive EMPD were all significantly higher than noninvasive EMPD (P < .0001). Ki-67 labeling index as well as the cyclin D1 score was also significantly higher in invasive than noninvasive lesions of EMPD. These results demonstrated that androgen receptor and androgen-producing enzymes were both associated with cell cycle regulation and subsequently the invasiveness of EMPD lesions and could also indicate those above as potential markers of invasive potentials in EMPD.
    Matched MeSH terms: Forkhead Transcription Factors/metabolism
  10. Rafieerad A, Yan W, Sequiera GL, Sareen N, Abu-El-Rub E, Moudgil M, et al.
    Adv Healthc Mater, 2019 08;8(16):e1900569.
    PMID: 31265217 DOI: 10.1002/adhm.201900569
    Inflammation is tightly linked to tissue injury. In regenerative medicine, immune activation plays a key role in rejection of transplanted stem cells and reduces the efficacy of stem cell therapies. Next-generation smart biomaterials are reported to possess multiple biologic properties for tissue repair. Here, the first use of 0D titanium carbide (Ti3 C2 ) MXene quantum dots (MQDs) for immunomodulation is presented with the goal of enhancing material-based tissue repair after injury. MQDs possess intrinsic immunomodulatory properties and selectively reduce activation of human CD4+ IFN-γ+ T-lymphocytes (control 87.1 ± 2.0%, MQDs 68.3 ± 5.4%) while promoting expansion of immunosuppressive CD4+ CD25+ FoxP3+ regulatory T-cells (control 5.5 ± 0.7%, MQDs 8.5 ± 0.8%) in a stimulated lymphocyte population. Furthermore, MQDs are biocompatible with bone marrow-derived mesenchymal stem cells and induced pluripotent stem cell-derived fibroblasts. Finally, Ti3 C2 MQDs are incorporated into a chitosan-based hydrogel to create a 3D platform with enhanced physicochemical properties for stem cell delivery and tissue repair. This composite hydrogel demonstrates increased conductivity while maintaining injectability and thermosensitivity. These findings suggest that this new class of biomaterials may help bridge the translational gap in material and stem cell-based therapies for tissue repair and treatment of inflammatory and degenerative diseases.
    Matched MeSH terms: Forkhead Transcription Factors/metabolism
  11. Kang IN, Musa M, Harun F, Junit SM
    Biochem Genet, 2010 Feb;48(1-2):141-51.
    PMID: 20094846 DOI: 10.1007/s10528-009-9306-7
    The FOXE1 gene was screened for mutations in a cohort of 34 unrelated patients with congenital hypothyroidism, 14 of whom had thyroid dysgenesis and 18 were normal (the thyroid status for 2 patients was unknown). The entire coding region of the FOXE1 gene was PCR-amplified, then analyzed using single-stranded conformational polymorphism, followed by confirmation by direct DNA sequencing. DNA sequencing analysis revealed a heterozygous A>G transition at nucleotide position 394 in one of the patients. The nucleotide transition changed asparagine to aspartate at codon 132 in the highly conserved region of the forkhead DNA binding domain of the FOXE1 gene. This mutation was not detected in a total of 104 normal healthy individuals screened. The binding ability of the mutant FOXE1 protein to the human thyroperoxidase (TPO) promoter was slightly reduced compared with the wild-type FOXE1. The mutation also caused a 5% loss of TPO transcriptional activity.
    Matched MeSH terms: Forkhead Transcription Factors/genetics*
  12. Yip WK, Abdullah MA, Yusoff SM, Seow HF
    Clin Exp Immunol, 2009 Mar;155(3):412-22.
    PMID: 19220831 DOI: 10.1111/j.1365-2249.2008.03793.x
    The pathological significance of the mechanisms of tumour immune-evasion and/or immunosuppression, such as loss of T cell signalling and increase in regulatory T cells (T(regs)), has not been well established in the nasopharyngeal carcinoma (NPC) microenvironment. To evaluate the T(reg) immunophenotypes in tumour-infiltrating lymphocytes (TILs), we performed a double-enzymatic immunostaining for detection of forkhead box P3 (FoxP3) and other markers including CD4, CD8, and CD25 on 64 NPC and 36 non-malignant nasopharyngeal (NP) paraffin-embedded tissues. Expression of CD3 zeta and CD3 epsilon was also determined. The prevalence of CD4(+)FoxP3(+) cells in CD4(+) T cells and the ratio of FoxP3(+)/CD8(+) were increased significantly in NPC compared with those in NP tissues (P < 0.001 and P = 0.025 respectively). Moreover, the ratio of FoxP3(+)/CD25(+)FoxP3(-) in NPC was significantly lower than that in NP tissues (P = 0.005), suggesting an imbalance favouring activated phenotype of T cells in NPC. A significant negative correlation between the abundance of FoxP3(+) and CD25(+)FoxP3(-) cells (P < 0.001) was also identified. When histological types of NPC were considered, a lower ratio of FoxP3(+)/CD25(+)FoxP3(-) was found in non-keratinizing and undifferentiated carcinomas. Increased CD4(+)FoxP3(+)/CD4(+) proportion and FoxP3(+)/CD8(+) ratio were associated with keratinizing squamous cell carcinoma. A reduced expression of CD3 zeta in TILs was found in 20.6% of the NPC tissues but none of the NP tissues. These data provide evidence for the imbalances of T(reg) and effector T cell phenotypes and down-regulation of signal-transducing molecules in TILs, supporting their role in suppression of immune response and immune evasion of NPC.
    Matched MeSH terms: Forkhead Transcription Factors/analysis
  13. Leong PP, Mohammad R, Ibrahim N, Ithnin H, Abdullah M, Davis WC, et al.
    Immunol Lett, 2006 Feb 15;102(2):229-36.
    PMID: 16246429
    Dysfunction of the host immune system in cancer patients can be due to a number of reasons including suppression of tumour associated antigen reactive lymphocytes by regulatory T (Treg) cells. In this study, we used flow cytometry to determine the phenotype and relative abundance of the tumour infiltrating lymphocytes (TILs) from 47 enzymatically dissociated tumour specimens from patients with infiltrating ductal carcinoma (IDC) of the breast. The expression of both effector and regulatory markers on the TILs were determined by using a panel of monoclonal antibodies. Analysis revealed CD8(+) T cells (23.4+/-2.1%) were predominant in TILs, followed by CD4(+) T cells (12.6+/-1.7%) and CD56(+) natural killer cells (6.4+/-0.7%). The CD4(+)/CD8(+) ratio was 0.8+/-0.9%. Of the CD8(+) cells, there was a higher number (68.4+/-3.5%) that expressed the effector phenotype, namely, CD8(+)CD28(+) and about 46% of this subset expressed the activation marker, CD25. Thus, a lower number of infiltrating CD8(+) T cells (31.6+/-2.8%) expressed the marker for the suppressor phenotype, CD8(+)CD28(-). Of the CD4(+) T cells, 59.6+/-3.9% expressed the marker for the regulatory phenotype, CD4(+)CD25(+). About 43.6+/-3.8% CD4(+)CD25(+) subset co-expressed both the CD152 and FOXP3, the Treg-associated molecules. A positive correlation was found between the presence of CD4(+)CD25(+) subset and age (> or =50 years old) (r=0.51; p=0.045). However, no significant correlation between tumour stage and CD4(+)CD25(+) T cells was found. In addition, we also found that the CD4(+)CD25(-) subset correlated with the expression of the nuclear oestrogen receptor (ER)-alpha in the tumour cells (r=0.45; p=0.040). In conclusion, we detected the presence of cells expressing the markers for Tregs (CD4(+)CD25(+)) and suppressor (CD8(+)CD28(-)) in the tumour microenvironment. This is the first report of the relative abundance of Treg co-expressing CD152 and FOXP3 in breast carcinoma.
    Matched MeSH terms: Forkhead Transcription Factors/analysis
  14. Lim A, Tan D, Price P, Kamarulzaman A, Tan HY, James I, et al.
    AIDS, 2007 Jul 31;21(12):1525-34.
    PMID: 17630546
    To examine the relationships between blood CD4 natural regulatory T (Treg) cells, plasma HIV RNA level, CD4 T-cell count and immune activation in untreated HIV-infected patients and immunodeficient patients beginning antiretroviral therapy (ART), using a novel phenotype to define Treg cells (CD25CD127CD4). Data were compared with established Treg cell markers (FoxP3, CTLA-4 and GITR).
    Matched MeSH terms: Forkhead Transcription Factors/blood
  15. Mohamad Shah NS, Salahshourifar I, Sulong S, Wan Sulaiman WA, Halim AS
    BMC Genet, 2016 Feb 11;17:39.
    PMID: 26868259 DOI: 10.1186/s12863-016-0345-x
    BACKGROUND: Nonsyndromic orofacial clefts are one of the most common birth defects worldwide. It occurs as a result of genetic or environmental factors. This study investigates the genetic contribution to nonsyndromic cleft lip and/or palate through the analysis of family pedigrees. Candidate genes associated with the condition were identified from large extended families from the Malay population.

    RESULTS: A significant nonparametric linkage (NPL) score was detected in family 100. Other suggestive NPL and logarithm of the odds (LOD) scores were attained from families 50, 58, 99 and 100 under autosomal recessive mode. Heterogeneity LOD (HLOD) score ≥ 1 was determined for all families, confirming genetic heterogeneity of the population and indicating that a proportion of families might be linked to each other. Several candidate genes in linkage intervals were determined; LPHN2 at 1p31, SATB2 at 2q33.1-q35, PVRL3 at 3q13.3, COL21A1 at 6p12.1, FOXP2 at 7q22.3-q33, FOXG1 and HECTD1 at 14q12 and TOX3 at 16q12.1.

    CONCLUSIONS: We have identified several novel and known candidate genes for nonsyndromic cleft lip and/or palate through genome-wide linkage analysis. Further analysis of the involvement of these genes in the condition will shed light on the disease mechanism. Comprehensive genetic testing of the candidate genes is warranted.

    Matched MeSH terms: Forkhead Transcription Factors/genetics
  16. Wong KK, Gascoyne DM, Brown PJ, Soilleux EJ, Snell C, Chen H, et al.
    Leukemia, 2014 Feb;28(2):362-72.
    PMID: 23884370 DOI: 10.1038/leu.2013.224
    We previously identified autoantibodies to the endocytic-associated protein Huntingtin-interacting protein 1-related (HIP1R) in diffuse large B-cell lymphoma (DLBCL) patients. HIP1R regulates internalization of cell surface receptors via endocytosis, a process relevant to many therapeutic strategies including CD20 targeting with rituximab. In this study, we characterized HIP1R expression patterns, investigated a mechanism of transcriptional regulation and its clinical relevance in DLBCL patients treated with immunochemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone, R-CHOP). HIP1R was preferentially expressed in germinal center B-cell-like DLBCL (P<0.0001) and inversely correlated with the activated B-cell-like DLBCL (ABC-DLBCL) associated transcription factor, Forkhead box P1 (FOXP1). HIP1R was confirmed as a direct FOXP1 target gene in ABC-DLBCL by FOXP1-targeted silencing and chromatin immunoprecipitation. Lower HIP1R protein expression (≤ 10% tumoral positivity) significantly correlated with inferior overall survival (OS, P=0.0003) and progression-free survival (PFS, P=0.0148) in R-CHOP-treated DLBCL patients (n=157). Reciprocal expression with ≥ 70% FOXP1 positivity defined FOXP1(hi)/HIP1R(lo) patients with particularly poor outcome (OS, P=0.0001; PFS, P=0.0016). In an independent R-CHOP-treated DLBCL (n=233) microarray data set, patients with transcript expression in lower quartile HIP1R and FOXP1(hi)/HIP1R(lo) subgroups exhibited worse OS, P=0.0044 and P=0.0004, respectively. HIP1R repression by FOXP1 is strongly associated with poor outcome, thus further understanding of FOXP1-HIP1R and/or endocytic signaling pathways might give rise to novel therapeutic options for DLBCL.
    Matched MeSH terms: Forkhead Transcription Factors/genetics*; Forkhead Transcription Factors/metabolism
  17. Wong KK, Gascoyne DM, Soilleux EJ, Lyne L, Spearman H, Roncador G, et al.
    Oncotarget, 2016 Aug 16;7(33):52940-52956.
    PMID: 27224915 DOI: 10.18632/oncotarget.9507
    FOXP2 shares partially overlapping normal tissue expression and functionality with FOXP1; an established diffuse large B-cell lymphoma (DLBCL) oncogene and marker of poor prognosis. FOXP2 is expressed in the plasma cell malignancy multiple myeloma but has not been studied in DLBCL, where a poor prognosis activated B-cell (ABC)-like subtype display partially blocked plasma cell differentiation. FOXP2 protein expression was detected in ABC-DLBCL cell lines, and in primary DLBCL samples tumoral FOXP2 protein expression was detected in both germinal center B-cell-like (GCB) and non-GCB DLBCL. In biopsies from DLBCL patients treated with immunochemotherapy (R-CHOP), ≥ 20% nuclear tumoral FOXP2-positivity (n = 24/158) correlated with significantly inferior overall survival (OS: P = 0.0017) and progression-free survival (PFS: P = 0.0096). This remained significant in multivariate analysis against either the international prognostic index score or the non-GCB DLBCL phenotype (P < 0.05 for both OS and PFS). Expression of BLIMP1, a marker of plasmacytic differentiation that is commonly inactivated in ABC-DLBCL, did not correlate with patient outcome or FOXP2 expression in this series. Increased frequency of FOXP2 expression significantly correlated with FOXP1-positivity (P = 0.0187), and FOXP1 co-immunoprecipitated FOXP2 from ABC-DLBCL cells indicating that these proteins can co-localize in a multi-protein complex. FOXP2-positive DLBCL had reduced expression of HIP1R (P = 0.0348), which is directly repressed by FOXP1, and exhibited distinct patterns of gene expression. Specifically in ABC-DLBCL these were associated with lower expression of immune response and T-cell receptor signaling pathways. Further studies are warranted to investigate the potential functional cooperativity between FOXP1 and FOXP2 in repressing immune responses during the pathogenesis of high-risk DLBCL.
    Matched MeSH terms: Forkhead Transcription Factors/genetics; Forkhead Transcription Factors/metabolism*
  18. Wong WF, Kohu K, Nagashima T, Funayama R, Matsumoto M, Movahed E, et al.
    Mol Immunol, 2015 Dec;68(2 Pt A):223-33.
    PMID: 26350416 DOI: 10.1016/j.molimm.2015.08.012
    The Runx1 transcription factor cooperates with or antagonizes other transcription factors and plays essential roles in the differentiation and function of T lymphocytes. Previous works showed that Runx1 is expressed in peripheral CD4(+) T cells which level declines after T cell receptor (TCR) activation, and artificial deletion of Runx1 causes autoimmune lung disease in mice. The present study addresses the mechanisms by which Runx1 contributes to the maintenance of peripheral CD4(+) T cell quiescence. Microarray and quantitative RT-PCR analyses were employed to compare the transcriptome of Runx1 -/- CD4(+) T cells to those of unstimulated and TCR-stimulated Runx1 +/- cells. The results identified genes whose expression was modulated similarly by Runx1 deletion and TCR activation. Among them, genes encoding cytokines, chemokines, and Jak/STAT signaling molecules were substantially induced. In Runx1-deleted T cells, simultaneous increases in Il-17A and Rorγc, a known master gene in TH17 differentiation, were observed. In addition, we observed that the loss of Runx1 reduced the transcription of genes encoding quiescence-associated transcription factors, including Foxp1, Foxo1, and Klf2. Interestingly, we identified consensus Runx1 binding sites at the promoter regions of Foxp1, Foxo1, and Klf2 genes, which can be enriched by chromatin immunoprecipitation assay with an anti-Runx1 antibody. Therefore, we suggest that Runx1 may activate, directly or indirectly, the expression of quiescence-associated molecules and thereby contribute to the maintenance of quiescence in CD4(+) T cells.
    Matched MeSH terms: Forkhead Transcription Factors/genetics; Forkhead Transcription Factors/immunology*
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