10 results
Search Results
2. Genetic landscape of T cells identifies synthetic lethality for T-ALL.
- Author
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O'Meara, Connor P., Guerri, Lucia, Lawir, Divine-Fondzenyuy, Mateos, Fernando, Iconomou, Mary, Iwanami, Norimasa, Soza-Ried, Cristian, Sikora, Katarzyna, Siamishi, Iliana, Giorgetti, Orlando, Peter, Sarah, Schorpp, Michael, and Boehm, Thomas
- Subjects
WHOLE genome sequencing ,T cell differentiation ,GENETIC variation ,GENETIC testing ,CANCER cells ,T cells - Abstract
To capture the global gene network regulating the differentiation of immature T cells in an unbiased manner, large-scale forward genetic screens in zebrafish were conducted and combined with genetic interaction analysis. After ENU mutagenesis, genetic lesions associated with failure of T cell development were identified by meiotic recombination mapping, positional cloning, and whole genome sequencing. Recessive genetic variants in 33 genes were identified and confirmed as causative by additional experiments. The mutations affected T cell development but did not perturb the development of an unrelated cell type, growth hormone-expressing somatotrophs, providing an important measure of cell-type specificity of the genetic variants. The structure of the genetic network encompassing the identified components was established by a subsequent genetic interaction analysis, which identified many instances of positive (alleviating) and negative (synthetic) genetic interactions. Several examples of synthetic lethality were subsequently phenocopied using combinations of small molecule inhibitors. These drugs not only interfered with normal T cell development, but also elicited remission in a model of T cell acute lymphoblastic leukaemia. Our findings illustrate how genetic interaction data obtained in the context of entire organisms can be exploited for targeted interference with specific cell types and their malignant derivatives. O'Meara et al. utilize a panel of zebrafish mutants to perform a whole organism genetic interaction screen, examining the network regulating T cell differentiation. The authors use a T cell acute lymphoblastic leukemia (T-ALL) model to integrate the effects of small molecule inhibitors of the T cell differentiation pathway and establish a combination therapy for T-ALL in juvenile zebrafish. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
3. Insights into the expanding intestinal phenotypic spectrum of SOCS1 haploinsufficiency and therapeutic options.
- Author
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Rodari, Marco M., Cazals-Hatem, Dominique, Uzzan, Mathieu, Martin Silva, Nicolas, Khiat, Anis, Ta, Minh Chau, Lhermitte, Ludovic, Touzart, Aurore, Hanein, Sylvain, Rouillon, Cléa, Joly, Francisca, Elmorjani, Adrienne, Steffann, Julie, Cerf-Bensussan, Nadine, Parlato, Marianna, and Charbit-Henrion, Fabienne
- Subjects
REGULATORY T cells ,INTESTINES ,KILLER cells ,T cells ,GENETIC testing ,ADRENAL insufficiency - Abstract
Purpose: Hyper activation of the JAK-STAT signaling underlies the pathophysiology of many human immune–mediated diseases. Herein, the study of 2 adult patients with SOCS1 haploinsufficiency illustrates the severe and pleomorphic consequences of its impaired regulation in the intestinal tract. Methods: Two unrelated adult patients presented with gastrointestinal manifestations, one with Crohn's disease-like ileo-colic inflammation refractory to anti-TNF and the other with lymphocytic leiomyositis causing severe chronic intestinal pseudo-occlusion. Next-generation sequencing was used to identify the underlying monogenic defect. One patient received anti-IL-12/IL-23 treatment while the other received the JAK1 inhibitor, ruxolitinib. Peripheral blood, intestinal tissues, and serum samples were analyzed before-and-after JAK1 inhibitor therapy using mass cytometry, histology, transcriptomic, and Olink assay. Results: Novel germline loss-of-function variants in SOCS1 were identified in both patients. The patient with Crohn-like disease achieved clinical remission with anti-IL-12/IL-23 treatment. In the second patient with lymphocytic leiomyositis, ruxolitinib induced rapid resolution of the obstructive symptoms, significant decrease of the CD8+ T lymphocyte muscular infiltrate, and normalization of serum and intestinal cytokines. Decreased frequencies of circulating Treg cells, MAIT cells, and NK cells, with altered CD56
bright :CD16lo :CD16hi NK subtype ratios were not modified by ruxolitinib. Conclusion: SOCS1 haploinsufficiency can result in a broad spectrum of intestinal manifestations and need to be considered as differential diagnosis in cases of severe treatment-refractory enteropathies, including the rare condition of lymphocytic leiomyositis. This provides the rationale for genetic screening and considering JAK inhibitors in such cases. [ABSTRACT FROM AUTHOR]- Published
- 2023
- Full Text
- View/download PDF
4. T cell ALL in a child with Ataxia telangiectasia; diagnosis and management challenges.
- Author
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Ahmed, Omaima, Felimban, Yara, and Almehdar, Abeer
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ATAXIA telangiectasia ,T cells ,HEMATOLOGIC malignancies ,DIAGNOSIS ,GENETIC testing - Abstract
Ataxia telangiectasia (A-T) is a rare childhood autosomal recessive neurodegenerative chromosomalin stability disorder. It is characterized by high risk of hematological malignancies with T-cell phenotype being the most common, which can present first before the diagnosis of A-T made. The chromosomalin stability in A-T increases the toxicity to radio-chemotherapeutic agents, creating the treatment modification challenges and the deviation from the optimal management protocols. In this case report, we present a 14-month-old boy diagnosed as T cell –ALL. Based on his early presentation, family history of childhood lymphoma, and high AFP, inherited predisposition was suspected, and genetic testing confirms A-T. This report represents the crucial part of clinical suspicion of A-T in similar cases as well as highlighting the importance of an early A-T diagnosis that prevents toxic death due to the extensive regimen of radio- chemotherapeutic agents. The report summarizes the toxicity and modification challenges during management with literature review for the chemotherapy modification experience in such cases. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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5. Current State of Pediatric Cardio-Oncology: A Review.
- Author
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Brickler, Molly, Raskin, Alexander, and Ryan, Thomas D.
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CARDIOVASCULAR disease prevention ,SURVIVAL ,SMALL molecules ,CARDIOTOXICITY ,CARDIOVASCULAR diseases risk factors ,PUBLIC health surveillance ,HEART transplantation ,ANTHRACYCLINES ,IMMUNE checkpoint inhibitors ,CELLULAR therapy ,PEDIATRICS ,GENETIC testing ,TUMORS in children ,PEDIATRIC cardiology ,RISK assessment ,CARDIAC pacing ,DRUG side effects ,T cells ,CANCER patient medical care ,IMMUNOTHERAPY ,EARLY diagnosis ,CHILDREN - Abstract
The landscape of pediatric oncology has dramatically changed over the course of the past several decades with five-year survival rates surpassing 80%. Anthracycline therapy has been the cornerstone of many chemotherapy regimens for pediatric patients since its introduction in the 1960s, and recent improved survival has been in large part due to advancements in chemotherapy, refinement of supportive care treatments, and development of novel therapeutics such as small molecule inhibitors, chimeric antigen receptor T-cell therapy, and immune checkpoint inhibitors. Unfortunately, many cancer-targeted therapies can lead to acute and chronic cardiovascular pathologies. The range of cardiotoxicity can vary but includes symptomatic or asymptotic heart failure, arrhythmias, coronary artery disease, valvar disease, pericardial disease, hypertension, and peripheral vascular disease. There is lack of data guiding primary prevention and treatment strategies in the pediatric population, which leads to substantial practice variability. Several important future research directions have been identified, including as they relate to cardiac disease, prevention strategies, management of cardiovascular risk factors, risk prediction, early detection, and the role of genetic susceptibility in development of cardiotoxicity. Continued collaborative research will be key in advancing the field. The ideal model for pediatric cardio-oncology is a proactive partnership between pediatric cardiologists and oncologists in order to better understand, treat, and ideally prevent cardiac disease in pediatric oncology patients. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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6. Association between Polymorphisms of the IL-23R Gene and Allergic Rhinitis in a Chinese Han Population
- Author
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Hu, Di, Hu, Guohua, Zhu, Jing, Shen, Yang, Kang, Houyong, and Hong, Suling
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ALLERGIC rhinitis ,GENETIC polymorphisms ,INTERLEUKIN receptors ,CELL differentiation ,OTOLARYNGOLOGY ,MEDICAL genetics ,CYTOKINES ,CHINESE people ,DISEASES - Abstract
Objective: Polymorphism of the interleukin-23 receptor gene corresponds with susceptibility to several immune-related diseases. For the terminal differentiation of IL-17-producing effector T-helper cells in vivo, the interleukin-23 receptor gene is of vital importance. As shown recently, Th17 cells probably have a great influence on the pathogenesis of allergic airway diseases. Our intention was to establish an association between polymorphisms in the IL-23R gene and allergic rhinitis (AR) in the Chinese Han population. Methods: We included 358 AR patients and 407 control Chinese subjects in a case-control comparison. The study involved obtaining blood samples for DNA extraction genotyping and determination of 4 selected single-nucleotide polymorphisms in IL-23R by performing PCR restriction fragment length polymorphism analysis (PCR-RFLP). Results: A substantially growing prevalence of the homozygous rs7517847 GG genotype and G allele appeared in the AR patients unlike that observed in the control individuals (P<0.001). In addition, substantially high frequencies of the GGCA and GGCG haplotypes were observed in the AR patients, unlike that observed in the control individuals (P<0.05). The results suggest that the AGTG haplotype may provide protection against AR (P<0.001). Conclusions: To the best of our knowledge, this is the first study to demonstrate an important association between polymorphisms in IL-23R and AR in the Chinese Han population. A strong association between rs7517847 in a SNP of IL-23R, and AR was identified. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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7. A forward genetic screen reveals roles for Nfkbid, Zeb1, and Ruvbl2 in humoral immunity.
- Author
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Arnold, Carrie N., Pirie, Elaine, Dosenovic, Pia, Mclnerney, Gerald M., Xia, Yu, Wang, Nathaniel, Li, Xiaohong, Siggs, Owen M., Karlsson Hedestam, Gunilla B., and Beutler, Bruce
- Subjects
GENETIC testing ,HUMORAL immunity ,CHEMICAL mutagenesis ,LABORATORY mice ,IMMUNE response ,B cells ,T cells - Abstract
Using chemical germ-line mutagenesis, we screened mice for defects in the humoral immune response to a type II T-independent immunogen and an experimental alphavirus vector. A total of 26 mutations that impair humoral immunity were recovered, and 19 of these mutations have been positionally cloned. Among the phenovariants were bumble, cellophane, and Worker ascribed to mutations in Nfkbid, Zebl, and Ruvbl2, respectively. We show that IKBNS, the nuclear IxB-like protein encoded by Nfkbid, is required for the development of marginal zone and peritoneal B-1 B cells and additionally required for extrafollicular antibody responses to T-independent and -dependent immunogens. Zeb1 is also required for marginal zone and peritoneal B-1 B-cell development as well as T-cell development, germinal center formation, and memory B-cell responses. Finally, Ruvbl2 is required for T-cell development and maximal T-dependent antibody responses. Collectively, the mutations that we identified give us insight into the points at which disruption of an antibody response can occur. All of the mutations identified to date directly affect lymphocyte development or function; none have an exclusive effect on cells of the innate immune system. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
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8. Association of CD1A +622 T/C, +737 G/C and CD1E +6129 A/G Genes Polymorphisms with Multiple Sclerosis.
- Author
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Jamshidian, Azam, Nikseresht, Ali-Reza, Vessal, Mahmood, and Kamali-Sarvestani, Eskandar
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IMMUNOGLOBULINS ,T cells ,GLYCOLIPIDS ,AMPLIFIED fragment length polymorphism ,GENETIC testing - Abstract
Antibodies and specific T cells to glycolipids have been found in MS patients. CD1 molecules are involved in presentation of lipid antigens to T-cells. Therefore, functional polymorphisms in two CD1 genes (+622 T/C and +737 G/C in CD1A along with +6129 A/G in CD1E) might be associated with susceptibility to MS. First, 351 MS patients and 342 controls were enrolled in this study. Allele-specific oligonucleotide polymerase chain reaction and PCR-RFLP methods were used for genotyping. The frequency of CD1A genotypes was not different between cases and controls. However, investigating females, the frequency of CD1A*01 allele was significantly higher in patients with PP-MS compared to controls (p = 0.028) as well as to RR-MS and SP-MS (p = 0.042 and 0.021, respectively). The distribution of CD1E +6129 A allele (CD1E*01) and CD1E*01/01 genotype is more frequent in normal controls in comparison with MS patients (p = 0.001 and p = 0.0003, respectively). In addition, after categorization of study groups according to disease types, differences between alleles and genotypes of CD1E gene polymorphism remained significant for RR-MS patients compared to those of normal controls (p = 0.0001 and p = 0.0003, respectively). CD1E and CD1A genes may be involved in networks which determine susceptibility to RR-MS and PP-MS, respectively. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
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9. Genetic Analysis Reveals Rare Variants in T-Cell Response Gene MR1 Associated with Poor Overall Survival after Urothelial Cancer Diagnosis.
- Author
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Bang, Lisa, Shivakumar, Manu, Garg, Tullika, Kim, Dokyoon, and Vallet, Sonia
- Subjects
CANCER genetics ,CANCER prognosis ,CANCER prevention ,EPIDEMIOLOGY of cancer ,SEQUENCE analysis ,AGE distribution ,GENETIC testing ,GERM cells ,DISEASE incidence ,REGRESSION analysis ,HEALTH outcome assessment ,URINARY organs ,TRANSITIONAL cell carcinoma ,SEX distribution ,GENOMES ,SURVIVAL analysis (Biometry) ,KAPLAN-Meier estimator ,T cells ,ELECTRONIC health records ,SMOKING ,PHENOTYPES ,LONGITUDINAL method - Abstract
Simple Summary: The objectives of this study were to identify rare germline variant associations in urothelial carcinoma of the bladder (UC) incidence and to determine its association with clinical outcomes. Our analysis reveals that individuals with MR1 rare germline variants had significantly worse OS than those without any, and those with ADGRL2 variants were slightly more likely to have UC compared to a control cohort matched for age, sex, and smoking status. These associations, using models incorporating known environmental covariates and using well-defined clinical phenotypes, highlight several candidates for prognostic indicator genes for the differential presentation of UC. These associations highlight several candidate genes that have the potential to explain clinical disparities in UC and predict UC outcomes. Urothelial carcinoma of the bladder (UC) is the fifth most common cancer in the United States. Germline variants, especially rare germline variants, may account for a portion of the disparity seen among patients in terms of UC incidence, presentation, and outcomes. The objectives of this study were to identify rare germline variant associations in UC incidence and to determine its association with clinical outcomes. Using exome sequencing data from the DiscovEHR UC cohort (n = 446), a European-ancestry, North American population, the complex influence of germline variants on known clinical phenotypes were analyzed using dispersion and burden metrics with regression tests. Outcomes measured were derived from the electronic health record (EHR) and included UC incidence, age at diagnosis, and overall survival (OS). Consequently, key rare variant association genes were implicated in MR1 and ADGRL2. The Kaplan–Meier survival analysis reveals that individuals with MR1 germline variants had significantly worse OS than those without any (log-rank p-value = 3.46 × 10
−7 ). Those with ADGRL2 variants were found to be slightly more likely to have UC compared to a matched control cohort (FDR q-value = 0.116). These associations highlight several candidate genes that have the potential to explain clinical disparities in UC and predict UC outcomes. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
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10. Glutaminyl cyclase is an enzymatic modifier of the CD47- SIRP[alpha] axis and a target for cancer immunotherapy
- Author
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Logtenberg, Meike E. W., Jansen, J. H. Marco, Raaben, Matthijs, Toebes, Mireille, Franke, Katka, Brandsma, Arianne M., and Matlung, Hanke L.
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Cancer treatment -- Research ,Cancer cells -- Research ,Transglutaminases -- Research ,Antibodies -- Usage ,Gene expression -- Research ,Biochemistry ,T cells ,Intelligence gathering ,Cancer ,Tumors ,Cetuximab ,Cell death ,Peptides ,Macrophages ,Protein binding ,Apoptosis ,Immunotherapy ,Genetic testing ,Enzymes ,Novels ,Biological sciences ,Health - Abstract
Cancer cells can evade immune surveillance through the expression of inhibitory ligands that bind their cognate receptors on immune effector cells. Expression of programmed death ligand 1 in tumor microenvironments is a major immune checkpoint for tumor-specific T cell responses as it binds to programmed cell death protein-1 on activated and dysfunctional T cells.sup.1. The activity of myeloid cells such as macrophages and neutrophils is likewise regulated by a balance between stimulatory and inhibitory signals. In particular, cell surface expression of the CD47 protein creates a 'don't eat me' signal on tumor cells by binding to SIRP[alpha] expressed on myeloid cells.sup.2-5. Using a haploid genetic screen, we here identify glutaminyl-peptide cyclotransferase-like protein (QPCTL) as a major component of the CD47-SIRP[alpha] checkpoint. Biochemical analysis demonstrates that QPCTL is critical for pyroglutamate formation on CD47 at the SIRP[alpha] binding site shortly after biosynthesis. Genetic and pharmacological interference with QPCTL activity enhances antibody-dependent cellular phagocytosis and cellular cytotoxicity of tumor cells. Furthermore, interference with QPCTL expression leads to a major increase in neutrophil-mediated killing of tumor cells in vivo. These data identify QPCTL as a novel target to interfere with the CD47 pathway and thereby augment antibody therapy of cancer. QPCTL is a modifier of CD47-SIRP[alpha] binding and its blockade enhances macrophage- and neutrophil-mediated antibody dependent cellular cytotoxicity towards tumor cells., Author(s): Meike E. W. Logtenberg [sup.1] , J. H. Marco Jansen [sup.2] , Matthijs Raaben [sup.3] , Mireille Toebes [sup.1] , Katka Franke [sup.4] , Arianne M. Brandsma [sup.2] , [...]
- Published
- 2019
- Full Text
- View/download PDF
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