Gain-of-Function STAT1 Mutation With Familial Lymphadenopathy and Hodgkin Lymphoma.
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ABSTRACT:
SUBMITTER: Henrickson SE
PROVIDER: S-EPMC6503099 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:STAT1 gain-of-function (GOF) is a primary immunodeficiency typically characterized by chronic mucocutaneous candidiasis (CMC), recurrent respiratory infections, and autoimmunity. Less commonly, also immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX)-like syndromes with CMC, and combined immunodeficiency without CMC have been described. Recently, our group and others have shown that different mutation-specific mechanisms underlie STAT1 GOF in vitro, including faster nuclear accumulation (R274W), and reduced mobility (R321, N574I) to near immobility in the nucleus (T419R) upon IFN? stimulation. In this work, we evaluated the transcriptomic fingerprint of the aforementioned STAT1 GOF mutants (R274W, R321S, T419R, and N574I) relative to STAT1 wild-type upon IFN? stimulation in an otherwise isogenic cell model. The majority of genes up-regulated in wild-type STAT1 cells were significantly more up-regulated in cells expressing GOF mutants, except for T419R. In addition to the common interferon regulated genes (IRG), STAT1 GOF mutants up-regulated an additional set of genes, that were in part shared with other GOF mutants or mutation-specific. Overall, R274W and R321S transcriptomes clustered with STAT1 WT, while T419R and N574I had a more distinct fingerprint. We observed reduced frequency of canonical IFN? activation site (GAS) sequences in promoters of genes up-regulated by all the STAT1 GOF mutants, suggesting loss of DNA binding specificity for the canonical GAS consensus. Interestingly, the T419R mutation, expected to directly increase the affinity for DNA, showed the most pronounced effects on the transcriptome. T419R STAT1 dysregulated more non-IRG than the other GOF mutants and fewer GAS or degenerate GAS promotor sequences could be found in the promoter regions of these genes. In conclusion, our work confirms hyperactivation of common sets of IFN?-induced genes in STAT1 GOF with additional dysregulation of mutation-specific genes, in line with the earlier observed mutation-specific mechanisms. Binding to more degenerate GAS sequences is proposed as a mechanism toward transcriptional dysregulation in R274W, R321S, and N574I. For T419R, an increased interaction with the DNA is suggested to result in a broader and less GAS-specific response. Our work indicates that multiple routes leading to STAT1 GOF are associated with common and private transcriptomic fingerprints, which may contribute to the phenotypic variation observed in vivo.
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2023-07-19 | GSE211445 | GEO
Project description:Oesophageal candidiasis is a common, usually self-limiting opportunistic infection, but long-term infection with Candida is known to predispose to oral and oesophageal squamous cell cancer (SCC). Permissive factors that lead to immune deficiencies can underlie persistent or recurring candidiasis, called chronic mucocutaneous candidiasis (CMC). Secondary immune deficiencies are most often due to human immunodeficiency virus (HIV) infection, antibiotic use and immunosuppressive treatment (steroids, chemotherapy). Inborn errors of the immune system (primary immune deficiencies) can present with isolated CMC known as CMC disease (CMCD), which is most often found in patients with autoimmune polyendocrinopathy syndrome type 1 (APS1)/APECED or in patients with an underlying gain-of-function STAT1 mutation (GOF-STAT1).To describe a new form of inherited/familial CMC with a high risk for developing squamous cell carcinoma of the oesophagus, due to a gain-of-function mutation in the STAT1 gene.This report describes a family of patients with CMC with confirmed GOF-STAT1 mutation. These patients usually present with CMCD in childhood, have severe oral and oesophageal candidiasis accompanied by severe difficulty swallowing, chest pain, heartburn, and are at risk of developing oral and/or oesophageal SCC. This case series describes six patients in three generations of the same family, two of whom developed and died of SCC. We recommend regular endoscopic surveillance to detect early oesophageal neoplasia in patients with CMCD as well as urgent endoscopy in symptomatic patients.CMC is not a well-recognised condition in gastroenterology practice and clinicians need to be aware of the genetics of the condition as well as the risk for oesophageal cancer so that they can counsel their patients and arrange surveillance appropriately.
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Project description:Disease-causing mutations in genes encoding transcription factors (TF) are frequent in hematopoietic malignancies and might affect TF-interactions with respective DNA-binding motifs. Here, we report the characterization of a recurrent somatic mutation c.295T>C in the IRF4 gene in classic Hodgkin lymphoma (cHL) leading to a C99R exchange. IRF4-C99R is located in the center of the IRF4 alpha3-recognition helix contacting the DNA 5´-GAAA-3´ IRF consensus sequence. IRF4-C99R fundamentally alters IRF4 DNA-binding, combining loss-of-binding at canonical IRF motifs and neomorph gain-of-binding at canonical and non-canonical IRF composite elements (CEs), in particular AP-1-IRF-CEs (AICEs). In line, IRF4-C99R profoundly impairs IRF4-dependent plasma cell induction, and specifically up-regulates degenerate-AICE-dependent distinct cHL disease-characteristic genes. These data document an unprecedented mutation-induced shift of TF binding specificity and its impact for lymphoma pathogenesis and TF modulation.
2023-07-19 | GSE211444 | GEO
Project description:Disease-causing mutations in genes encoding transcription factors (TF) are frequent in hematopoietic malignancies and might affect TF-interactions with respective DNA-binding motifs. Here, we report the characterization of a recurrent somatic mutation c.295T>C in the IRF4 gene in classic Hodgkin lymphoma (cHL) leading to a C99R exchange. IRF4-C99R is located in the center of the IRF4 alpha3-recognition helix contacting the DNA 5´-GAAA-3´ IRF consensus sequence. IRF4-C99R fundamentally alters IRF4 DNA-binding, combining loss-of-binding at canonical IRF motifs and neomorph gain-of-binding at canonical and non-canonical IRF composite elements (CEs), in particular AP-1-IRF-CEs (AICEs). In line, IRF4-C99R profoundly impairs IRF4-dependent plasma cell induction, and specifically up-regulates degenerate-AICE-dependent distinct cHL disease-characteristic genes. These data document an unprecedented mutation-induced shift of TF binding specificity and its impact for lymphoma pathogenesis and TF modulation.
2023-07-19 | GSE211913 | GEO
Project description:Disease-causing mutations in genes encoding transcription factors (TF) are frequent in hematopoietic malignancies and might affect TF-interactions with respective DNA-binding motifs. Here, we report the characterization of a recurrent somatic mutation c.295T>C in the IRF4 gene in classic Hodgkin lymphoma (cHL) leading to a C99R exchange. IRF4-C99R is located in the center of the IRF4 alpha3-recognition helix contacting the DNA 5´-GAAA-3´ IRF consensus sequence. IRF4-C99R fundamentally alters IRF4 DNA-binding, combining loss-of-binding at canonical IRF motifs and neomorph gain-of-binding at canonical and non-canonical IRF composite elements (CEs), in particular AP-1-IRF-CEs (AICEs). In line, IRF4-C99R profoundly impairs IRF4-dependent plasma cell induction, and specifically up-regulates degenerate-AICE-dependent distinct cHL disease-characteristic genes. These data document an unprecedented mutation-induced shift of TF binding specificity and its impact for lymphoma pathogenesis and TF modulation.
2023-07-19 | GSE211443 | GEO
Project description:Disease-causing mutations in genes encoding transcription factors (TF) are frequent in hematopoietic malignancies and might affect TF-interactions with respective DNA-binding motifs. Here, we report the characterization of a recurrent somatic mutation c.295T>C in the IRF4 gene in classic Hodgkin lymphoma (cHL) leading to a C99R exchange. IRF4-C99R is located in the center of the IRF4 alpha3-recognition helix contacting the DNA 5´-GAAA-3´ IRF consensus sequence. IRF4-C99R fundamentally alters IRF4 DNA-binding, combining loss-of-binding at canonical IRF motifs and neomorph gain-of-binding at canonical and non-canonical IRF composite elements (CEs), in particular AP-1-IRF-CEs (AICEs). In line, IRF4-C99R profoundly impairs IRF4-dependent plasma cell induction, and specifically up-regulates degenerate-AICE-dependent distinct cHL disease-characteristic genes. These data document an unprecedented mutation-induced shift of TF binding specificity and its impact for lymphoma pathogenesis and TF modulation.
2023-07-19 | GSE211441 | GEO
Project description:STAT1 gain-of-function (GOF) variants lead to defective Th17 cell development and chronic mucocutaneous candidiasis (CMC), but frequently also to autoimmunity. STAT1 GOF mutations result in hyperphosphorylation and delayed dephosphorylation of STAT1. However, how the delayed dephosphorylation exactly causes the increased expression of STAT1-dependent genes, and how the intracellular signal transduction from cytokine receptors is affected, remains unknown. In this study we show that the circulating levels of IFN-α in STAT1 GOF patients were not persistently elevated. Nevertheless, the interferon signature was evident even in the patient with low or undetectable IFN-α levels. Chromatin immunoprecipitation (ChIP) experiments showed that the active chromatin mark H3K4me3, was significantly enriched in areas associated with interferon-stimulated genes in STAT1 GOF cells in comparison to normal cells. This suggests that GOF STAT1, while binding to chromatin, promotes epigenetic changes compatible with higher gene expression and elevated reactivity to type I interferons, and interferon-related autoimmunity. We suggest that epigenetic rewiring may be responsible for treatment failure of JAK1/2 inhibitors in certain patients. We also found that after IL-21 stimulation the balance of p-STAT3/p-STAT1 was significantly impaired in patients, which could potentially be applied as a diagnostic test for STAT1 GOF.
2019-05-31 | GSE120580 | GEO
Project description:STAT1 gain-of-function (GOF) is a primary immunodeficiency typically characterized by chronic mucocutaneous candidiasis (CMC), recurrent respiratory infections and autoimmunity. Less commonly, also immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX)-like syndromes with CMC, and combined immunodeficiency without CMC have been described. Recently, our group and others have shown that different mutation-specific mechanisms underlie STAT1 GOF in vitro, including faster nuclear accumulation (R274W), and reduced mobility (R321, N574I) to near immobility in the nucleus (T419R) upon IFNγ stimulation. In this work, we evaluated the transcriptomic fingerprint of the aforementioned STAT1 GOF mutants (R274W, R321S, T419R, and N574I) relative to STAT1 wild-type upon IFNγ stimulation in an otherwise isogenic cell model. The majority of genes up-regulated in wild-type STAT1 cells were significantly more up-regulated in cells expressing GOF mutants, except for T419R. In addition to the common interferon regulated genes (IRG), STAT1 GOF mutants up-regulated an additional set of genes, that were in part shared with other GOF mutants or mutation-specific. Overall, R274W and R321S transcriptomes clustered with STAT1 WT, while T419R and N574I had a more distinct fingerprint. We observed reduced frequency of canonical GAS sequences in promoters of genes up-regulated by all the STAT1 GOF mutants, suggesting loss of DNA binding specificity for the canonical GAS consensus. Interestingly, the T419R mutation, expected to directly increase the affinity for DNA, showed the most pronounced effects on the transcriptome. T419R STAT1 dysregulated more non-IRG than the other GOF mutants and fewer GAS or degenerate GAS promotor sequences could be found in the promoter regions of these genes. In conclusion: our work confirms hyperactivation of common sets of IFNγ-induced genes in STAT1 GOF with additional dysregulation of mutation-specific genes, in line with the earlier observed mutation-specific mechanisms. Binding to more degenerate GAS sequences is proposed as a mechanism towards transcriptional dysregulation in R274W, R321S, and N574I. For T419R, an increased interaction with the DNA is suggested to result in a broader and less GAS-specific response. Our work indicates that multiple routes leading to STAT1 GOF are associated with common and private transcriptomic fingerprints, which may contribute to the phenotypic variation observed in vivo.
2021-02-09 | GSE166392 | GEO