NFKB1 gene single-nucleotide polymorphisms: implications for graft-versus-host disease in allogeneic hematopoietic stem cell transplantation

Kuba, Adam; Raida, Ludek; Mrázek, František; Schneiderová, Petra; Kriegová, Eva; Langová, Kateřina; Fürst, Tomáš; Fürstová, Jana; Faber, Edgar; Papajík, Tomáš

doi:10.1007/s00277-020-03935-5

Cited by 7 publications

(3 citation statements)

References 45 publications

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“…Together, inflammatory mediators (IL-17 and CCL20) and SASP factors such as IL-1 and IL-6 function in a self-amplifying loop to induce alopecia and dermatitis in irradiated animals [41]. Interestingly, senescence and SASP induction have been closely associated with the pathogenesis of cGVHD [7,42]. Consistent with that, expression of the senescence-associated protein p16 was observed in the liver of allografted mice, which was strikingly diminished upon treatment with DQ.…”

Section: Discussionmentioning

confidence: 58%

Therapeutic Potential of a Senolytic Approach in a Murine Model of Chronic GVHD

Raman

Chêne

Nicco

et al. 2023

Biology

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Graft-versus-host disease (GVHD) is a life-threatening systemic complication of allogeneic hematopoietic stem cell transplantation (HSCT) characterized by dysregulation of T and B cell activation and function, scleroderma-like features, and multi-organ pathology. The treatment of cGVHD is limited to the management of symptoms and long-term use of immunosuppressive therapy, which underscores the need for developing novel treatment approaches. Notably, there is a striking similarity between cytokines/chemokines responsible for multi-organ damage in cGVHD and pro-inflammatory factors, immune modulators, and growth factors secreted by senescent cells upon the acquisition of senescence-associated secretory phenotype (SASP). In this pilot study, we questioned the involvement of senescent cell-derived factors in the pathogenesis of cGVHD triggered upon allogeneic transplantation in an irradiated host. Using a murine model that recapitulates sclerodermatous cGVHD, we investigated the therapeutic efficacy of a senolytic combination of dasatinib and quercetin (DQ) administered after 10 days of allogeneic transplantation and given every 7 days for 35 days. Treatment with DQ resulted in a significant improvement in several physical and tissue-specific features, such as alopecia and earlobe thickness, associated with cGVHD pathogenesis in allograft recipients. DQ also mitigated cGVHD-associated changes in the peripheral T cell pool and serum levels of SASP-like cytokines, such as IL-4, IL-6 and IL-8Rα. Our results support the involvement of senescent cells in the pathogenesis of cGVHD and provide a rationale for the use of DQ, a clinically approved senolytic approach, as a potential therapeutic strategy.

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Section: Discussionmentioning

confidence: 58%

Therapeutic Potential of a Senolytic Approach in a Murine Model of Chronic GVHD

Raman

Chêne

Nicco

et al. 2023

Biology

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“…Tranilast, an Nf-κb and Txnip inhibitor, was found to reduce cGVHD development in MHC-matched, miHA-mismatched mice ( 118 ). A very recent study of SNPs in the NF-κB1 gene found that two specific SNPs in this gene were associated with aGVHD and mortality after transplant ( 119 ). Therefore, Nf-κb clearly plays a role in GVHD, with primary effects on T cell proliferation, cytokine production, and Treg differentiation.…”

Section: Transcription Factors Which Separate Gvhd and Gvl Effectsmentioning

confidence: 99%

Dissecting the regulatory network of transcription factors in T cell phenotype/functioning during GVHD and GVT

Harris

Karimi

2023

Front. Immunol.

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Transcription factors play a major role in regulation and orchestration of immune responses. The immunological context of the response can alter the regulatory networks required for proper functioning. While these networks have been well-studied in canonical immune contexts like infection, the transcription factor landscape during alloactivation remains unclear. This review addresses how transcription factors contribute to the functioning of mature alloactivated T cells. This review will also examine how these factors form a regulatory network to control alloresponses, with a focus specifically on those factors expressed by and controlling activity of T cells of the various subsets involved in graft-versus-host disease (GVHD) and graft-versus-tumor (GVT) responses.

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“…If refractory to steroids, first choice is ruxolitinib and second choice other immunosuppressive treatments such as ECP, ibrutinib, rituximab, or sirolimus [ 12 ]. The reason why some HCT patients develop more severe cGVHD is not well understood, although some studies have sought to associate genetic polymorphisms with cGVHD [ 13 – 16 ]. Previous studies have associated SNPs mapped to genes with cGVHD incidence including C-X-C motif chemokine receptor 3 ( CXCR3 ), C–C motif chemokine receptor 6 ( CCR6 ), FGFR1 oncogene partner ( FGFR10P ), interleukin 10 ( IL10 ), interleukin 1 receptor type 1 ( IL1R1 ), nuclear factor kappa B subunit 1 ( NFKB1 ), heparanase ( HSPE ), and cytotoxic T-lymphocyte associated protein 4 ( CTLA4 ) [ 13 , 15 – 17 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of single nucleotide polymorphisms (SNPs) associated with chronic graft-versus-host disease in patients undergoing allogeneic hematopoietic cell transplantation

Mougeot,

Beckman,

Hovan

et al. 2023

Support Care Cancer

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Introduction Chronic graft-versus-host disease (cGVHD) is a debilitating side effect of allogeneic hematopoietic cell transplantation (HCT), affecting the quality of life of patients. We used whole exome sequencing to identify candidate SNPs and complete a multi-marker gene-level analysis using a cohort of cGVHD( +) (N = 16) and cGVHD( −) (N = 66) HCT patients. Methods Saliva samples were collected from HCT patients (N = 82) pre-conditioning in a multi-center study from March 2011 to May 2018. Exome sequencing was performed and FASTQ files were processed for sequence alignments. Significant SNPs were identified by logistic regression using PLINK2v3.7 and Fisher’s exact test. One cGVHD( −) patient sample was excluded from further analysis since no SNP was present in at least 10% of the sample population. The FUMA platform’s SNP2GENE was utilized to annotate SNPs and generate a MAGMA output. Chromatin state visualization of lead SNPs was completed using Epilogos tool. FUMA’s GENE2FUNC was used to obtain gene function and tissue expression from lead genomic loci. Results Logistic regression classified 986 SNPs associated with cGVHD( +). SNP2GENE returned three genomic risk loci, four lead SNPs, 48 candidate SNPs, seven candidate GWAS tagged SNPs, and four mapped genes. Fisher’s exact test identified significant homozygous genotypes of four lead SNPs (p < 0.05). GENE2FUNC analysis of multi-marker SNP sets identified one positional gene set including lead SNPs for KANK1 and KDM4C and two curated gene sets including lead SNPs for PTPRD, KDM4C, and/or KANK1. Conclusions Our data suggest that SNPs in three genes located on chromosome 9 confer genetic susceptibility to cGVHD in HCT patients. These genes modulate STAT3 expression and phosphorylation in cancer pathogenesis. The findings may have implications in the modulation of pathways currently targeted by JAK inhibitors in cGVHD clinical trials.

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NFKB1 gene single-nucleotide polymorphisms: implications for graft-versus-host disease in allogeneic hematopoietic stem cell transplantation

Cited by 7 publications

References 45 publications

Therapeutic Potential of a Senolytic Approach in a Murine Model of Chronic GVHD

Therapeutic Potential of a Senolytic Approach in a Murine Model of Chronic GVHD

Dissecting the regulatory network of transcription factors in T cell phenotype/functioning during GVHD and GVT

Identification of single nucleotide polymorphisms (SNPs) associated with chronic graft-versus-host disease in patients undergoing allogeneic hematopoietic cell transplantation

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