Germline variants in children with hematological cancer
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ABSTRACT:
PROVIDER: EGAS00001006907 | EGA |
REPOSITORIES: EGA
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Project description:Cellular immunotherapy has proven to be effective in the treatment of hematological cancers by donor lymphocyte infusion after allogeneic hematopoietic stem cell transplantation and more recently by targeted therapy with chimeric antigen or T-cell receptor-engineered T-cells. However, dependent on the tissue distribution of the antigens that are targeted, anti-tumor responses can be accompanied by undesired side effects. Therefore, detailed tissue distribution analysis is essential to estimate efficacy and toxicity of candidate targets for immunotherapy of hematological malignancies. In this study, we performed microarray gene expression analysis of hematological malignancies of different origins, healthy hematopoietic cells and various non-hematopoietic cell types from organs that are often targeted in detrimental immune responses after allogeneic stem cell transplantation leading to graft-versus-host disease. Non-hematopoietic cells were also cultured in the presence of IFN-γ to analyze gene expression under inflammatory circumstances. Gene expression was investigated by Illumina HT12.0 microarrays and quality control analysis was performed to confirm the cell-type origin and exclude contamination of non-hematopoietic cell samples with peripheral blood cells. Microarray data were validated by quantitative RT-PCR showing strong correlation between both platforms. Detailed gene expression profiles were generated for various minor histocompatibility antigens and B-cell surface antigens to illustrate the value of the microarray dataset to estimate efficacy and toxicity of candidate targets for immunotherapy. In conclusion, our microarray database provides a relevant platform to analyze and select candidate antigens with hematopoietic (lineage)-restricted expression as potential targets for immunotherapy of hematological cancers. Microarray gene expression analysis was performed on hematological malignancies of different origins and their healthy hematopoietic counterparts as well as on healthy non-hematopoietic cell types from organs that are often targeted in Graft-versus-Host Disease (166 samples in total). Various non-hematopoietic cell types were cultured in the presence of IFN-γ or T-cell culture supernatant to allow gene expression analysis under inflammatory conditions. Malignant and healthy hematopoietic cells were isolated by flow cytometry based on expression of specific surface markers and healthy non-hematopoietic cell types were isolated or cultured from tissue biopsies or surgically removed specimen. Various non-hematopoietic cell types were in vitro cultured for 4 days in the presence of IFN-γ or T-cell culture supernatant to mimic inflammation. The dataset allows comparison of gene expression between hematological malignancies and healthy non-hematopoietic cell types to estimate efficacy and toxicity of immunotherapeutic targets for hematological malignancies. Total RNA was isolated from (malignant) hematopoietic cells isolated by flow cytometry based on expression of specific surface markers and from healthy non-hematopoietic cell types isolated or cultured from tissue biopsies or surgically removed specimen. From various non-hematopoietic cell types, total RNA was also isolated after 4 days of in vitro culture in the presence of IFN-γ or T-cell culture supernatant.
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Project description:Function-damaging variants in the TRIO gene are enriched in individuals with neurodevelopmental disorders (NDDs). TRIO encodes a cytoskeletal regulatory protein with three catalytic domains – two guanine exchange factor (GEF) domains, GEF1 and GEF2, and a kinase domain, as well as several accessory domains that have not been extensively studied. Disease variants in the GEF1 domain or the nine adjacent spectrin repeats (SRs) are enriched in NDDs, suggesting that dysregulated GEF1 activity is linked to these disorders. We provide evidence here that the Trio SRs interact intramolecularly with the GEF1 domain to inhibit its activity. We demonstrate that SRs 6-9 decrease GEF1 catalytic activity both in vitro and in cells and show that NDD-associated variants in the SR8 and GEF1 domains relieve this autoinhibitory constraint. Our results from chemical cross-linking and BioLayer Interferometry indicate that the SRs primarily contact the PH region of the GEF1 domain, reducing GEF1 binding to Rac1. Together, our findings reveal a key regulatory mechanism that is commonly disrupted in multiple NDDs and may offer a new target for therapeutic intervention for TRIO-associated NDDs.
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Project description:Cellular immunotherapy has proven to be effective in the treatment of hematological cancers by donor lymphocyte infusion after allogeneic hematopoietic stem cell transplantation and more recently by targeted therapy with chimeric antigen or T-cell receptor-engineered T-cells. However, dependent on the tissue distribution of the antigens that are targeted, anti-tumor responses can be accompanied by undesired side effects. Therefore, detailed tissue distribution analysis is essential to estimate efficacy and toxicity of candidate targets for immunotherapy of hematological malignancies. In this study, we performed microarray gene expression analysis of hematological malignancies of different origins, healthy hematopoietic cells and various non-hematopoietic cell types from organs that are often targeted in detrimental immune responses after allogeneic stem cell transplantation leading to graft-versus-host disease. Non-hematopoietic cells were also cultured in the presence of IFN-γ to analyze gene expression under inflammatory circumstances. Gene expression was investigated by Illumina HT12.0 microarrays and quality control analysis was performed to confirm the cell-type origin and exclude contamination of non-hematopoietic cell samples with peripheral blood cells. Microarray data were validated by quantitative RT-PCR showing strong correlation between both platforms. Detailed gene expression profiles were generated for various minor histocompatibility antigens and B-cell surface antigens to illustrate the value of the microarray dataset to estimate efficacy and toxicity of candidate targets for immunotherapy. In conclusion, our microarray database provides a relevant platform to analyze and select candidate antigens with hematopoietic (lineage)-restricted expression as potential targets for immunotherapy of hematological cancers. Microarray gene expression analysis was performed on hematological malignancies of different origins and their healthy hematopoietic counterparts as well as on healthy non-hematopoietic cell types from organs that are often targeted in Graft-versus-Host Disease (166 samples in total). Various non-hematopoietic cell types were cultured in the presence of IFN-γ or T-cell culture supernatant to allow gene expression analysis under inflammatory conditions. Malignant and healthy hematopoietic cells were isolated by flow cytometry based on expression of specific surface markers and healthy non-hematopoietic cell types were isolated or cultured from tissue biopsies or surgically removed specimen. Various non-hematopoietic cell types were in vitro cultured for 4 days in the presence of IFN-γ or T-cell culture supernatant to mimic inflammation. The dataset allows comparison of gene expression between hematological malignancies and healthy non-hematopoietic cell types to estimate efficacy and toxicity of immunotherapeutic targets for hematological malignancies.
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