Category: Article scientifique

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

Abstract

Objectives 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.

July 2018 / Annals of the Rheumatic Diseases – Raphael Carapito, Christine Carapito, Aurore Morlon, Nicodème Paul, Alvaro Sebastian Vaca Jacome, Ghada Alsaleh, Véronique Rolli, Ouria Tahar, Ismail Aouadi, Magali Rompais, François Delalande, Angélique Pichot, Philippe Georgel, Laurent Messer, Jean Sibilia, Sarah Cianferani, Alain Van Dorsselaer, Seiamak Bahram

Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells

Abstract

Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD+ leukemia cells. This synergized with the allogeneic CD8+ T cell response, leading to long-term survival in six mouse models of FLT3-ITD+ AML. Sorafenib-related IL-15 production caused an increase in CD8+CD107a+IFN-γ+ T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro. Human FLT3-ITD+ AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8+ T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD-mutant AML relapse, an otherwise fatal complication after allo-HCT.

March 2018 / Nature Medicine – Mathew NR, Baumgartner F, Braun L, O’Sullivan D, Thomas S, Waterhouse M, Müller TA, Hanke K, Taromi S, Apostolova P, Illert AL, Melchinger W, Duquesne S, Schmitt-Graeff A, Osswald L, Yan KL, Weber A, Tugues S, Spath S, Pfeifer D, Follo M, Claus R, Lübbert M, Rummelt C, Bertz H, Wäsch R, Haag J, Schmidts A1, Schultheiss M, Bettinger D, Thimme R, Ullrich E, Tanriver Y, Vuong GL, Arnold R, Hemmati P, Wolf D, Ditschkowski M, Jilg C, Wilhelm K, Leiber C, Gerull S, Halter J, Lengerke C, Pabst T, Schroeder T, Kobbe G, Rösler W, Doostkam S, Meckel S, Stabla K, Metzelder SK, Halbach S, Brummer T, Hu Z, Dengjel J, Hackanson B, Schmid C, Holtick U, Scheid C, Spyridonidis A, Stölzel F, Ordemann R, Müller LP, Sicre-de-Fontbrune F, Ihorst G, Kuball J, Ehlert JE, Feger D, Wagner EM, Cahn JY, Schnell J, Kuchenbauer F, Bunjes D, Chakraverty R, Richardson S, Gill S, Kröger N, Ayuk F, Vago L, Ciceri F, Müller AM, Kondo T, Teshima T, Klaeger S, Kuster B, Kim DDH, Weisdorf D, van der Velden W, Dörfel D, Bethge W, Hilgendorf I, Hochhaus A, Andrieux G, Börries M, Busch H, Magenau J, Reddy P, Labopin M, Antin JH, Henden AS, Hill GR, Kennedy GA, Bar M, Sarma A, McLornan D, Mufti G, Oran B, Rezvani K, Shah O, Negrin RS, Nagler A, Prinz M, Burchert A, Neubauer A, Beelen D, Mackensen A, von Bubnoff N, Herr W4, Becher B, Socié G, Caligiuri MA, Ruggiero E, Bonini C, Häcker G, Duyster J, Finke J, Pearce E, Blazar BR, Zeiser R

Influence of Blood Pressure and Calcineurin Inhibitors on Kidney Function After Heart or Liver Transplantation

Abstract

BACKGROUND:

Chronic kidney disease is common after heart or liver transplantation, with calcineurin inhibitors (CNI) considered the key contributor. A possible influence of posttransplant blood pressure has not been extensively examined.

METHODS:

Data from adult recipients of a first heart or liver transplant were analyzed regarding the relationship between blood pressure at year 1, renal function at year 5, and CNI therapy.

RESULTS:

Whereas we confirmed the well-known detrimental effect of increased 1-year systolic blood pressure on 5-year kidney graft survival, heart or liver graft survival were not affected. However, among 2,534 heart transplant recipients with good renal function at year 1, increasing systolic blood pressure at year 1 was associated with higher rates of poor renal function at year 5 posttransplant. This association was confirmed on multivariate analysis overall (odds ratio [OR] 1.25 per 20 mmHg increment, P<0.001) and within subgroups. Similar results were observed in 1,822 liver transplant recipients (OR 1.35, P<0.001). Neither the type of CNI nor CNI dose or trough level at year 1 showed a significant association with kidney function at year 5.

CONCLUSIONS:

One-year blood pressure was identified as the major modifiable risk factor associated with deteriorating kidney function between years 1 to 5 after heart or liver transplantation.

December 2017 / Transplantation – Morath C, Opelz G, Döhler B, Zeier M, Süsal C

HLA Matching in Pediatric Kidney Transplantation: HLA Poorly Matched Living Donor Transplants Versus HLA Well-Matched Deceased Donor Transplants

Abstract
In this registry analysis, pediatric kidney graft survival of well HLA matched kidneys from deceased donors compares favorably with that of grafts from poorly HLA matched living donors, increasing the debate over counselling and allocation policies. Supplemental digital content is available in the text.

November 2017 / Transplantation – Opelz G, Döhler B, Middleton D et Süsal C

More informations: http://journals.lww.com/transplantjournal/Abstract/2017/11000/HLA_Matching_in_Pediatric_Kidney_Transplantation__.27.aspx

Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond–like features

Abstract

Shwachman-Diamond syndrome (SDS) (OMIM #260400) is a rare inherited bone marrow failure syndrome (IBMFS) that is primarily characterized by neutropenia and exocrine pancreatic insufficiency. Seventy-five to ninety percent of patients have compound heterozygous loss-of-function mutations in the Shwachman-Bodian-Diamond syndrome (sbds) gene. Using trio whole-exome sequencing (WES) in an sbds-negative SDS family and candidate gene sequencing in additional SBDS-negative SDS cases or molecularly undiagnosed IBMFS cases, we identified 3 independent patients, each of whom carried a de novo missense variant in srp54 (encoding signal recognition particle 54 kDa). These 3 patients shared congenital neutropenia linked with various other SDS phenotypes. 3D protein modeling revealed that the 3 variants affect highly conserved amino acids within the GTPase domain of the protein that are critical for GTP and receptor binding. Indeed, we observed that the GTPase activity of the mutated proteins was impaired. The level of SRP54 mRNA in the bone marrow was 3.6-fold lower in patients with SRP54-mutations than in healthy controls. Profound reductions in neutrophil counts and chemotaxis as well as a diminished exocrine pancreas size in a SRP54-knockdown zebrafish model faithfully recapitulated the human phenotype. In conclusion, autosomal dominant mutations in SRP54, a key member of the cotranslation protein-targeting pathway, lead to syndromic neutropenia with a Shwachman-Diamond–like phenotype. October 2017 / The Journal of Clinical Investigation – Carapito R, Konantz M, Paillard C, Miao Z, Pichot A, S. Leduc M, Yang Y, L. Bergstrom K, H. Mahoney D, L. Shardy D, Alsaleh G, Naegely L, Kolmer A, Paul N, Hanauer A, Rolli V, S. Müller J, Alghisi E, Sauteur L, Macquin C,  Morlon A, Sancho C.S, Amati-Bonneau P, Procaccio V, Mosca-Boidron A.-L., Marle N, Osmani N, Lefebvre O, G. Goetz J, Unal S, A. Akarsu N, Radosavljevic M, Chenard M-P, Rialland F, Grain A, Béné M-C, Eveillard M, Vincent M, Guy J,  Faivre L, Thauvin-Robinet C, Thevenon J, Myers K, D. Fleming M, Shimamura A, Bottollier-Lemallaz E, Westhof E, Lengerke C, Isidor B et Bahram S

Endothelial precursor cell cross-match using Tie-2-enriched spleen cells

Abstract

Background

Non-HLA antibodies against human endothelial progenitor cells (EPC) in pre-transplant recipient serum can have a deleterious influence on the graft. EPC enriched from peripheral blood have been commonly used for EPC cross-matching. In the present study, we describe cross-matches using EPC enriched from fresh or frozen-thawed spleen cell preparations, thereby widening the sample source for deceased-donor cross-matching and retrospective studies.

Methods

EPC cross-matches were performed retrospectively using spleen cells and the flow cytometric XM-ONE cross-match test kit.

Results

Healthy controls (n = 28) showed no IgG antibodies against EPC. When sera of 11 random dialysis patients were studied, 2 patients (18%) exhibited IgG EPC antibodies. When pre-transplant sera of 20 kidney graft recipients with good long-term graft outcome (serum creatinine 1.0 ± 0.2 mg/dL measured 2463 ± 324 days post-transplant) were investigated using frozen-thawed and then separated Tie-2-enriched spleen cells of the original transplant donor, 3 patients (15%) had pre-transplant IgG EPC antibodies. When pre-transplant sera of 5 patients with intra-operative graft loss were studied employing the original donor spleen cells, 4 (80%) patients showed IgG EPC antibodies.

Conclusions

Cross-matches with spleen cell-derived EPC using the XM-ONE assay are technically possible. Our very preliminary experience suggests clinical relevance.

© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Septembre 2017 / Clinical Transplantation – Daniel V, Süsal C, Scherer S, Tran H, Gombos P, Trojan K, Sadeghi M, Morath C, Opelz G.