Multi-omics dataset to decipher the complexity of drug resistance in diffuse large B-cell lymphoma

Abstract The prognosis of patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) remains unsatisfactory and, despite major advances in genomic studies, the biological mechanisms underlying chemoresistance are still poorly understood. We conducted for the first time a large-scale differential multi-omics investigation on DLBCL patient’s samples in order to identify new biomarkers that could early identify patients at risk of R/R disease and to identify new targets that could determine chemorefractoriness. We compared a well-characterized cohort of R/R versus chemosensitive DLBCL patients by combining label-free quantitative proteomics and targeted RNA sequencing performed on the same tissues samples. The cross-section of both data levels allowed extracting a sub-list of 22 transcripts/proteins pairs whose expression levels significantly differed between the two groups of patients. In particular, we identified significant targets related to tumor metabolism (Hexokinase 3), microenvironment (IDO1, CXCL13), cancer cells proliferation, migration and invasion (S100 proteins) or BCR signaling pathway (CD79B). Overall, this study revealed several extremely promising biomarker candidates related to DLBCL chemorefractoriness and highlighted some new potential therapeutic drug targets. The complete datasets have been made publically available and should constitute a valuable resource for the future research

Multi-OMICS analyses unveil STAT1 as a potential modifier gene in mevalonate kinase deficiency

International audienceObjectives The objective of the present study was to explain why two siblings carrying both the same homozygous pathogenic mutation for the autoinflammatory disease hyper IgD syndrome, show opposite phenotypes, that is, the first being asymptomatic, the second presenting all classical characteristics of the disease.Methods Where single omics (mainly exome) analysis fails to identify culprit genes/mutations in human complex diseases, multiomics analyses may provide solutions, although this has been seldom used in a clinical setting. Here we combine exome, transcriptome and proteome analyses to decipher at a molecular level, the phenotypic differences between the two siblings.Results This multiomics approach led to the identification of a single gene—STAT1—which harboured a rare missense variant and showed a significant overexpression of both mRNA and protein in the symptomatic versus the asymptomatic sister. This variant was shown to be of gain of function nature, involved in an increased activation of the Janus kinase/signal transducer and activator of transcription signalling (JAK/STAT) pathway, known to play a critical role in inflammatory diseases and for which specific biotherapies presently exist. Pathway analyses based on information from differentially expressed transcripts and proteins confirmed the central role of STAT1 in the proposed regulatory network leading to an increased inflammatory phenotype in the symptomatic sibling.Conclusions This study demonstrates the power of a multiomics approach to uncover potential clinically actionable targets for a personalised therapy. In more general terms, we provide a proteogenomics analysis pipeline that takes advantage of subject-specific genomic and transcriptomic information to improve protein identification and hence advance individualised medicine.This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

Migrations conceptuelles

Les travaux relatifs aux questions informationnelles et communicationnelles associées aux organisations se sont multipliés depuis une quinzaine d’années, au travers de nombreuses journées d’études, colloques et ouvrages…, la revue « Communication et Organisation » occupant une place centrale dans cette dynamique. Une étude des productions scientifiques des vingt dernières années montre que les objets étudiés se sont inscrits dans des espaces de plus en plus étendus. Interrogeant initialement les pratiques, politiques et stratégies de communication mises en œuvre au sein des organisations à partir des années 1980, la communication organisationnelle s’est progressivement constituée en cadre d’analyse. Montant en généralité, les travaux ont visé à mieux comprendre les organisations à partir des phénomènes de communication qui s’y développent. L’étude de la communication des organisations s’est ainsi étendue à l’observation des phénomènes communicationnels au sein des organisations, et à l’analyse des organisations par la communication. Nous avons choisi de qualifier comme « approches communicationnelles des organisations » (ACO) ce glissement paradigmatique qui vise à comprendre les organisations, leur fonctionnement et leurs dynamiques à partir des phénomènes de communication qui les structurent

Hemodynamic forces tune the arrest, adhesion and extravasation of circulating tumor cells

International audienc

Hemodynamic forces tune the arrest, adhesion and extravasation of circulating tumor cells

International audienc

Protein-altering MYH3 variants are associated with a spectrum of phenotypes extending to spondylocarpotarsal synostosis syndrome

International audienceSpondylocarpotarsal synostosis syndrome (SCT) is a rare Mendelian disorder (OMIM #272460) characterized by prenatal vertebral fusion, scoliosis, short stature and carpal and tarsal synostosis. SCT is typically known as an autosomal recessive disease caused by variants in the FLNB gene. The genetic basis of the rarer cases of vertical transmissions remains unknown. In two independent families with symptoms related to autosomal dominant SCT, we identified – by exome sequencing – two protein-altering variants in the embryonic myosin heavy chain 3 (MYH3) gene. As MYH3 variants are also associated with distal arthrogryposis (DA1, DA2A, DA2B) and autosomal dominant multiple pterygium syndromes (MPS), the present study expands the phenotypic spectrum of MYH3 variants to autosomal dominant SCT. Vertebral, carpal and tarsal fusions observed in both families further confirm that MYH3 plays a key role in skeletal development

The MHC class I MICA gene is a histocompatibility antigen in kidney transplantation

International audienceK idney transplantation is the only curative treatment for end-stage renal disease 1. The fact that the first successful kidney transplantation in man was between identical twins 2 , along with seminal work in animal models, hinted strongly that a single genetic locus does not govern the clinical outcome of a transplantation, no matter how relevant (such as the major histocompatibility complex (MHC), human leukocyte antigen (HLA)). Indeed, George Snell, in his landmark 1948 study 3 (as well as subsequent work by himself, and others), identified several dozen histocompatibility loci in the mouse 4 , although close to none has been identified to date in any species (including man). Fast forward to today, and, owing to the development and refinement of country-and continent-wide allocation processes, perioperative handling of the graft and patients, and selective immunosuppressive drugs that improve transplantation survival mainly by alleviating acute T cell-mediated rejection (TCMR), the number of kidney transplantations is continuously increasing worldwide. However, antibody-mediated rejection (ABMR) is recognized as a major cause of late transplantation failure, and its treatment remains challenging 5. In addition to the histological findings, a key feature of ABMR is the presence of donor-specific anti-HLA antibodies (DSA) 6. Nonetheless, in routine clinical care, cases meeting the histological criteria for ABMR but without detectable anti-HLA DSA could represent more than 50% of rejection events 7. These cases might be explained by the presence of pathogenic antibodies that are produced against other, non-HLA, histocompatibility antigens 8. MHC class I chain-related gene A (MICA; GenBank accession: NM_001177519), discovered almost 30 years ago 9 , encodes a polymorphic non-conventional MHC-encoded class I molecule 10. The MICA gene is located, within the HLA complex, 46 kb centromeric to the HLA-B locus 9. Close to 400 MICA alleles have been reported to date 10. The MICA glycoprotein (Uniprot accession: Q96QC4) is expressed on a restricted number of cell types, mainly epithelial and endothelial cells. MICA binds NKG2D, an activating receptor present on the surface of cytotoxic CD8 + αβ and γδ T lymphocytes as well as certain natural killer (NK) cells 10. Fifteen years ago Zou et al. 11 reported the first comprehensive study of the potential involvement of MICA in kidney transplant outcomes. That work, however, was focused only on anti-MICA antibodies and had no information on donor and recipient MICA (mis)matching, a situation that has persisted to date given that no study has analyzed simultaneously the sequence-based molecular MICA matching and the status of both anti-HLA and anti-MICA DSA in a large cohort for which information about all other relevant covariates was available and included in the final analysis (for review see refs. 12,13)

Matching for the non-conventional MHC-I MICA gene significantly reduces the incidence of acute and chronic GVHD

Graft-versus-host disease (GVHD) is among the most challenging complications in unrelated donor hematopoietic cell transplantation (HCT). The highly polymorphic "MHC class I chain-related gene A", MICA, encodes a stress-induced glycoprotein expressed primarily on epithelia. MICA interacts with the invariant activating receptor NKG2D; expressed by cytotoxic lymphocytes. The MICA gene is located in the MHC, next to HLA-B; hence MICA has the requisite attributes of a bona fide transplantation antigen. Using high-resolution sequence-based genotyping of MICA, we retrospectively analyzed the clinical impact of MICA mismatches in a multicenter cohort of 922 unrelated donor HLA-A, -B, -C, -DRB1, and -DQB1 10/10 allele-matched HCT. Among the 922 pairs, 113 (12.3%) were mismatched in MICA MICA mismatches were significantly associated with an increased incidence of grade III-IV acute GVHD (HR, 1.83; 95% CI, 1.50 to 2.23; P<0.001), chronic GVHD (HR, 1.50; 95% CI, 1.45 to 1.55; P<0.001) and non-relapse mortality (HR, 1.35; 95% CI, 1.24 to 1.46; P<0.001). The increased risk of GVHD was mirrored by a lower risk of relapse (HR, 0.50; 95% CI, 0.43 to 0.59; P<0.001), indicating a possible graft-versus-leukemia effect. In conclusion, when possible, selecting a MICA-matched donor significantly influences key clinical outcomes of HCT in which a marked reduction of GVHD is paramount. The tight linkage disequilibrium between MICA and HLA-B renders identifying a MICA-matched donor readily feasible in clinical practice