Ontology highlight
ABSTRACT:
PROVIDER: PRJNA637231 | ENA |
REPOSITORIES: ENA
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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.
2016-09-01 | E-GEOD-76340 | biostudies-arrayexpress
Project description:We used EZH2i-targeted hematological malignancies as an examples and focused on molecular characterization of EZH2 Y641 mutant hematological cell lines. We used the proteomic strategies and compared the protein expression level and lysine methylation level (including mono-, di-, and trimethylaiton) in EZH2 wild-type (EZH2 WT), EZH2 Y641N and Y641F (EZH2 MUT) cell lines.
2019-12-17 | PXD016779 | iProX
Project description:TET1/2/3 are methylcytosine dioxygenases regulating cytosine hydroxymethylation in the genome. Tet1 and Tet2 are abundantly expressed in HSC/HPCs and implicated in the pathogenesis of hematological malignancies. Tet2-deletion in mice causes myeloid malignancies, while Tet1-null mice develop B-cell lymphoma after an extended period of latency. Interestingly, TET1 and TET2 were often concomitantly down-regulated in acute B-lymphocytic leukemia. Here, we investigated the overlapping and non-redundant functions of Tet1/Tet2 in HSC maintenance and development of hematological malignancies using Tet1/2 double knockout (DKO) mice. DKO and Tet2-/- HSC/HPCs had overlapping and unique 5hmC and 5mC profiles and behaved differently. DKO mice exhibited strikingly decreased incidence and delayed onset of myeloid malignancies compared to Tet2-/- mice and in contrast developed lethal B-cell malignancies. Transcriptome analysis of DKO tumors revealed expression changes in many genes dysregulated in human B-cell malignancies, such as LMO2, BCL6 and MYC. These results highlight the critical roles of TET1 or TET2 individually and their cross-talks in the pathogenesis of hematological malignancies. Given the role of Tet proteins in 5mC oxidation, we employed a previously established chemical labeling and affinity purification method coupled with high-throughput sequencing (hMe-Seal) to profile the genome-wide distribution of 5hmC, as well as methylated DNA immunoprecipitation (MeDIP) coupled with high-throughput sequencing (MeDIP-seq) to profile 5mC using BM LK cells purified from young WT, Tet2-/- and DKO mice (6-10 wks old).
2015-11-12 | E-GEOD-73611 | biostudies-arrayexpress
Project description:Background: Causative genes are mostly unknown for the mismatch repair-proficient category of familial colorectal cancers designated as FCCTX. Recent evidence suggests shared susceptibility factors between colorectal and hematological malignancies. Study design: We investigated 28 FCCTX families by exome sequencing, supplemented with whole genome sequencing, RNA-sequencing, and tumor studies to identify the predisposing genes. Guided by the findings, germline and somatic exomes of ~400 patients with acute leukemia, myelodysplastic syndrome, and myeloma were subsequently examined. Results: A family with hematological and solid malignancies revealed a truncating variant in the DEAH-box RNA helicase gene DHX40 co-segregating with disease in seven family members. Neoplastic tissues revealed no apparent “second hit”, implying a haploinsufficiency model of tumorigenesis. DHX40 siRNA-treated cell lines exhibited a 13% increase in aberrantly spliced transcripts vs. GAPDH-siRNA or non-target siRNA-treated cells. Two additional families showed truncating germline variants in the TDRD9 and TDRD5 genes encoding Tudor domain-containing RNA-binding proteins. In the hospital-based hematological series, 18% of germline and 28% of somatic exomes revealed possibly pathogenic DEAD/H box gene variants, including somatic variants of DHX40 in four. Conclusions: This study identifies DHX40, TDRD9, and TDRD5 as novel candidate genes for FCCTX predisposition. In the family segregating the truncating DHX40 variant, two carriers had hematological neoplasia, suggesting possible analogy to DDX41, a DEAD-box RNA helicase gene previously linked to myeloid malignancies. Our findings emphasize aberrant RNA metabolism behind FCCTX and hematological neoplasia.
2023-11-08 | GSE228991 | GEO
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.
2016-09-01 | GSE76340 | GEO
Project description:The TET2 gene encodes an α-ketoglutarate-dependent dioxygenase able to oxidize 5-methylcytosine into 5-hydroxymethylcytosine, which is a step toward active DNA demethylation. TET2 is frequently mutated in myeloid malignancies but also in B- and T-cell malignancies. TET2 somatic mutations are also identified in healthy elderly individuals with clonal hematopoiesis. Tet2-deficient mouse models showed widespread hematological differentiation abnormalities, including myeloid, T-cell, and B-cell malignancies. We show here that, similar to what is observed with constitutive Tet2-deficient mice, B-cell-specific Tet2 knockout leads to abnormalities in the B1-cell subset and a development of B-cell malignancies after long latency. Aging Tet2-deficient mice accumulate clonal CD19+ B220low immunoglobulin M+ B-cell populations with transplantable ability showing similarities to human chronic lymphocytic leukemia, including CD5 expression and sensitivity to ibrutinib-mediated B-cell receptor (BCR) signaling inhibition. Exome sequencing of Tet2-/- malignant B cells reveals C-to-T and G-to-A mutations that lie within single-stranded DNA-specific activation-induced deaminase (AID)/APOBEC (apolipoprotein B messenger RNA editing enzyme, catalytic polypeptide-like) cytidine deaminases targeted motif, as confirmed by the lack of a B-cell tumor in compound Tet2-Aicda-deficient mice. Finally, we show that Tet2 deficiency accelerates and exacerbates T-cell leukemia/lymphoma 1A-induced leukemogenesis. Together, our data establish that Tet2 deficiency predisposes to mature B-cell malignancies, which development might be attributed in part to AID-mediated accumulating mutations and BCR-mediated signaling. This accession concerns 46 transcriptomic experiments with Affymetrix Mouse 430-2 array..
2019-12-12 | E-MTAB-8501 | biostudies-arrayexpress
Project description:Concomitant multiple hematological malignancies are rare and challenging to diagnose. They represent a unique model to explore the multistep process of oncogenesis. Here, we report the unique case of 62 years-old man with cardiac tamponade as first manifestation of ALK negative anaplastic large T-cell lymphoma (ALK- ALCL). Following chemotherapy, he showed one year later ALK- ALCL concurrent with diffuse large B-cell lymphoma (DLBCL-NOS) and acute monoblastic leukemia (AML-M5) in a single excisional lymph node. Clinical, pathological and multiomics data (whole exome and targeted deep sequencing, spatial transcriptomics) were analyzed. Two somatic TET2 gene mutations at high allele burden were shared by all three neoplasms, uninvolved bone marrow and CD34+ hematopoietic stem and progenitor cells (HSPCs). Secondary hits characterized each malignancy. ALK- ALCL (pericardial and nodal) showed TP53 and LYN deleterious mutations, DLBCL-NOS disclosed KRAS, STAT6, CREBBP and ATM alterations and AML-M5 had JAK3, PPM1D, NF1 and KMT2D mutations and a complex karyotype. Furthermore we demonstrated that spatial transcriptomics can identify the specific signatures of the three neoplasms. Two TET2 mutations at high allele burden in CD34+HSPCs conferred the favorable soil and the genotoxic stress from chemotherapy likely contributed to multiple hematological malignancies oncogenesis. Our case confirms the pathogenetic link between clonal hematopoiesis and cytotoxic T-cell lymphoma, so far only suspected. Most importantly, this is the first study to document the oncogenic phylogeny of concurrent T-, B-, and myeloid neoplasms from CD34+ HSPCs clone(s) in a single specimen.
2023-03-17 | E-MTAB-12742 | biostudies-arrayexpress
Project description:U2AF1 mutations alter splice site recognition in hematological malignancies
| PRJNA253774 | ENA