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FOXP3 regulatory T cells on prognosis of breast cancer

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
Fulltext Revealing hidden genetic diagnoses in the ocular anterior segment disorders

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
Infantile vitiligo and alopecia in immunodysregulation polyendocrinopathy enteropathy X-linked syndrome

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
Characterization of mutations in the FOXE1 gene in a cohort of unrelated Malaysian patients with congenital hypothyroidism and thyroid dysgenesis

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*
Fulltext Discovery of candidate genes for nonsyndromic cleft lip palate through genome-wide linkage analysis of large extended families in the Malay population

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
Fulltext PIP4Ks impact on PI3K, FOXP3, and UHRF1 signaling and modulate human regulatory T cell proliferation and immunosuppressive activity

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
Reciprocal expression of the endocytic protein HIP1R and its repressor FOXP1 predicts outcome in R-CHOP-treated diffuse large B-cell lymphoma patients

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*
Fulltext FOXP2-positive diffuse large B-cell lymphomas exhibit a poor response to R-CHOP therapy and distinct biological signatures

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
The artificial loss of Runx1 reduces the expression of quiescence-associated transcription factors in CD4(+) T lymphocytes

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