Beta Locus Research Articles

Biallelic Loss of 7q34 (TRB) and 9p21.3 (CDKN2A/2B) in Adult Ph-Negative Acute T-Lymphoblastic Leukemia

Tumor cells of acute lymphoblastic leukemia (ALL) may have various genetic abnormalities. Some of them lead to a complete loss of certain genes. Our aim was to reveal biallelic deletions of genes in Ph–negative T-ALL. Chromosomal microarray analysis (CMA) was performed for 47 patients with de novo Ph–negative T-ALL, who received treatment according to RALL-2016m clinical protocol at the National Medical Research Center for Hematology (Moscow, Russia) from 2017 to 2023. Out of forty-seven patients, only three had normal molecular karyotype. The other 44 patients had multiple gains, losses, and copy neutral losses of heterozygosity. Biallelic losses were found in 14 patients (30%). In ten patients (21%), a biallelic deletion of 9p21.3 involved a different number of genes, however CDKN2A gene loss was noted in all ten cases. For seven patients (15%), a biallelic deletion of 7q34 was found, including two genes—PRSS1, PRSS2 located within the T-cell receptor beta (TRB) locus. A clonal rearrangement of the TRB gene was revealed in 6 out of 7 cases with 7q34 biallelic loss. Both biallelic deletions can be considered favorable prognostic factors, with an association with 9p21 being statistically significant (p = 0.01) and a trend for 7q34 (p = 0.12) being observed.

Comparative Study of T-Cell Repertoires after COVID-19 Immunization with Homologous or Heterologous Vaccine Booster.

Sequencing of the T-cell repertoire is an innovative method to assess the cellular responses after immunization. The purpose of this study was to compare T-cell repertoires after COVID-19 immunization with homologous (HOB) and heterologous (HEB) boosting. The study included 20 participants with a median age of 27.5 (IQR:23) years, who were vaccinated with one dose of the Ad26.COV2.S vaccine and were boosted with either Ad26.COV2.S (n = 10) or BNT162b2 (n = 10) vaccine. Analysis of the T-cell receptor beta locus (TCRβ) sequencing one month after the booster dose identified that the HEB compared to the HOB group exhibited a higher number of both total and COVID-19-related functional T-cell rearrangements [mean of total productive rearrangements (TPRs): 63151.8 (SD ± 18441.5) vs. 34915.4 (SD ± 11121.6), p = 0.001 and COVID-19-TPRs: 522.5 (SD ± 178.0) vs. 298.3 (SD ± 101.1), p = 0.003]. A comparison between the HOB and HEB groups detected no statistically significant differences regarding T-cell Simpson clonality [0.021 (IQR:0.014) vs. 0.019 (IQR:0.007)], richness [8734.5 (IQR:973.3) vs. 8724 (IQR:383.7)] and T-cell fraction [0.19 (IQR:0.08) vs. 0.18 (IQR:0.08)]. HEB also exhibited a substantially elevated humoral immune response one month after the booster dose compared to HOB [median antibody titer (IQR): 10115.0 U/mL (6993.0) vs. 1781.0 U/mL (1314.0), p = 0.001]. T-cell repertoire sequencing indicated that HEB had increased SARS-CoV-2-related T-cell rearrangements, which was in accordance with higher humoral responses and possibly conferring longer protection. Data from the present study indicate that the administration of different COVID-19 vaccines as a booster may provide better protection.

Genetic signature detected in T cell receptors from patients with severe COVID-19

Characterization of host genetic factors contributing to COVID-19 severity promises advances on drug discovery to fight the disease. Most genetic analyses to date have identified genome-wide significant associations involving loss-of-function variants for immune response pathways. Despite accumulating evidence supporting a role for Tcells in COVID-19 severity, no definitive genetic markers have been found to support an involvement of Tcell responses. We analyzed 205 whole exomes from both a well-characterized cohort of hospitalized severe COVID-19 patients and controls. Significantly enriched high impact alleles were found for 25 variants within the Tcell receptor beta (TRB) locus on chromosome 7. Although most of these alleles were found in heterozygosis, at least three or more in TRBV6-5, TRBV7-3, TRBV7-6, TRBV7-7, and TRBV10-1 suggested a possible TRB loss of function via compound heterozygosis. This loss-of-function in TRB genes supports suboptimal or dysfunctional Tcell responses as a major contributor to severe COVID-19 pathogenesis.

Evolution of T cell receptor beta loci in salmonids

Evolution of T cell receptor beta loci in salmonids

Evolution of T cell receptor beta loci in salmonids.

T-cell mediated immunity relies on a vast array of antigen specific T cell receptors (TR). Characterizing the structure of TR loci is essential to study the diversity and composition of T cell responses in vertebrate species. The lack of good-quality genome assemblies, and the difficulty to perform a reliably mapping of multiple highly similar TR sequences, have hindered the study of these loci in non-model organisms. High-quality genome assemblies are now available for the two main genera of Salmonids, Salmo and Oncorhynchus. We present here a full description and annotation of the TRB loci located on chromosomes 19 and 25 of rainbow trout (Oncorhynchus mykiss). To get insight about variations of the structure and composition of TRB locus across salmonids, we compared rainbow trout TRB loci with other salmonid species and confirmed that the basic structure of salmonid TRB locus is a double set of two TRBV-D-J-C loci in opposite orientation on two different chromosomes. Our data shed light on the evolution of TRB loci in Salmonids after their whole genome duplication (WGD). We established a coherent nomenclature of salmonid TRB loci based on comprehensive annotation. Our work provides a fundamental basis for monitoring salmonid T cell responses by TRB repertoire sequencing.

T-cell tolerant fraction as a predictor of immune-related adverse events

BackgroundImmune checkpoint inhibitor (ICI) therapies may cause unpredictable and potentially severe autoimmune toxicities termed immune-related adverse events (irAEs). Because T cells mediate ICI effects, T cell profiling may provide insight...

Minimal/Measurable Residual Disease Monitoring in Patients with Lymphoid Neoplasms by High-Throughput Sequencing of the T-Cell Receptor

High-throughput sequencing of the T-cell receptor beta (TRB) and gamma (TRG) loci is increasingly utilized due to its high sensitivity, specificity, and versatility in the diagnosis of various T-cell malignancies. Application of these technologies for tracking disease burden can be valuable in detecting recurrence, determining response to therapy, guiding future management of patients, and establishing endpoints for clinical trials. In this study, the performance of the commercially available LymphoTrack high-throughput sequencing assay was assessed for determining residual disease burden in patients with various T-cell malignancies. A custom bioinformatics pipeline and database was also developed to facilitate minimal/measurable residual disease analysis and clinical reporting. This assay demonstrated excellent test performance characteristics, achieving a sensitivity of 1 of 100,000 T-cell equivalents for the DNA inputs evaluated and high concordance with orthogonal testing methods. This assay was further utilized to correlate disease burden in several patients, demonstrating its potential utility for monitoring patients with T-cell malignancies.

Targeted long-read sequencing facilitates phased diploid assembly and genotyping of the human T cell receptor alpha, delta, and beta loci

T cell receptors (TCRs) recognize peptide fragments presented by the major histocompatibility complex (MHC) and are critical to Tcell-mediated immunity. Recent data have indicated that genetic diversity within TCR-encoding gene regions is underexplored, limiting understanding of the impact of TCR loci polymorphisms on TCR function in disease, even though TCR repertoire signatures (1) are heritable and (2) associate with disease phenotypes. To address this, we developed a targeted long-read sequencing approach to generate highly accurate haplotype resolved assemblies of the TCR beta (TRB) and alpha/delta (TRA/D) loci, facilitating the genotyping of all variant types, including structural variants. We validate our approach using two mother-father-child trios and 5 unrelated donors representing multiple populations. This resulted in improved genotyping accuracy and the discovery of 84 undocumented V, D, J, and C alleles, demonstrating the utility of this framework for improving our understanding of TCR diversity and function in disease.

Pancreatitis-Associated PRSS1-PRSS2 Haplotype Alters T-Cell Receptor Beta (TRB) Repertoire More Strongly Than PRSS1 Expression

Pancreatitis-Associated PRSS1-PRSS2 Haplotype Alters T-Cell Receptor Beta (TRB) Repertoire More Strongly Than PRSS1 Expression

Identification and characterization of the T cell receptor (TCR) repertoire of the cynomolgus macaque (Macaca Fascicularis)

BackgroundCynomolgus macaque (Macaca fascicularis) is an attractive animal model for the study of human disease and is extensively used in biomedical research. Cynomolgus macaques share behavioral, physiological, and genomic traits with humans and recapitulate human disease manifestations not observed in other animal species. To improve the use of the cynomolgus macaque model to investigate immune responses, we defined and characterized the T cell receptor (TCR) repertoire.ResultWe identified and analyzed the alpha (TRA), beta (TRB), gamma (TRG), and delta (TRD) TCR loci of the cynomolgus macaque. The expressed repertoire was determined using 22 unique lung samples from Mycobacterium tuberculosis infected cynomolgus macaques by single cell RNA sequencing. Expressed TCR alpha (TRAV) and beta (TRBV) variable region genes were enriched and identified using gene specific primers, which allowed their functional status to be determined. Analysis of the primers used for cynomolgus macaque TCR variable region gene enrichment showed they could also be used to amplify rhesus macaque (M. mulatta) variable region genes.ConclusionThe genomic organization of the cynomolgus macaque has great similarity with the rhesus macaque and they shared > 90% sequence similarity with the human TCR repertoire. The identification of the TCR repertoire facilitates analysis of T cell immunity in cynomolgus macaques.

A clonality analysis based on T-cell receptor beta and delta loci for high-grade gastrointestinal lymphoma in dogs.

Clonality assays based on antigen receptors are used as adjunct examinations in the diagnosis of lymphoproliferative diseases. We investigated the usefulness of the T-cell receptor beta (TRB) and T-cell receptor delta (TRD) loci in clonality assays for high-grade gastrointestinal (GI) lymphoma in dogs. For TRB, we used primers reported previously; for TRD, we designed primers for each of the V and J genes based on genomic sequences. Genomic DNA was extracted from 39 formalin-fixed, paraffin-embedded sections of high-grade GI lymphoma diagnosed histologically. The sensitivity of TRB and TRD primers for GI lymphoma was 41.0% and 38.5%, respectively, which was lower than the 82.1% sensitivity of T-cell receptor gamma (TRG) primers However, some cases that could not be detected using TRG primers had clonality with either TRB or TRD primers. We found the TRG locus to be more suitable as a first choice for the assay of canine lymphoma clonality than the TRB and TRD loci. However, the detection rate of T-cell clonality may be enhanced using TRB and TRD primers for lymphoma cases not detected using TRG primers.

Abstract 3604: PSC-derived T cells as a novel source of tumor antigen-specific T cell receptors

Abstract T cell receptor (TCR)-engineered T cells are a promising approach to cell therapy for cancer. TCRs targeting public tumor associated antigens (TAAs) offer the widest potential coverage of patients within and across tumor types. TAA-specific TCRs, however, are rare in the blood and when detected are frequently of low affinity due to negative selection of high-affinity self-antigen reactive T cells in the thymus. Here, we present a TCR discovery platform based on in vitro generation of T cells from human pluripotent stem cells (PSCs) using the previously described artificial thymic organoid (ATO) system. We hypothesized that ATO-derived T cells offer several advantages for TCR discovery including a novel TCR repertoire and the absence of negative selection against TAAs during T cell development. Sequencing of the TCR repertoire of polyclonal CD8+ T cells generated from a HLA-A*02:01+ PSC line confirmed low junctional diversity at both the TCR beta and alpha loci, consistent with our previous finding of low TdT expression during T cell development from PSCs and an enrichment for germline-like TCRs. We then interrogated this novel TCR repertoire for reactivity against two well-described HLA-A2-restricted epitopes of NY-ESO-1 and WT1, reactivities to which are rare in the blood. Following co-culture with artificial APCs, a surprisingly high frequency of antigen-specific T cells was detected by MHC-tetramer staining. From these, high frequency TCR clonotypes were functionally validated by reconstitution in Jurkat TCR-reporter cells. Interestingly, from a single experimental run multiple antigen-specific TCRs were validated (5 out of 10 tested clonotypes for NY-ESO-1, and 2 out of 5 for WT1). This finding was reproducible across independent experimental runs, yielding further validated TCRs against these targets. To benchmark relative TCR affinities, we compared a panel of 5 ATO-derived NY-ESO-1 TCRs with 4 blood-derived TCRs with the same specificity, as well as the affinity-enhanced 1G4 TCR. ATO-derived TCRs showed not only superior performance to their blood derived counterparts in peptide dilution assays, but TCRs were identified with equivalent or superior cytotoxicity to 1G4, including against cell lines with endogenous NY-ESO-1 expression. Comparative in vivo anti-tumor efficacy studies are in process. A similarly high level of specificity and cytotoxicity was observed for ATO-derived WT1-specific TCRs. Finally, we demonstrate proof-of-concept identification of TCRs specific to a prostate-specific antigen for which high quality TCRs have remained elusive. In conclusion, the PSC ATO TCR-discovery platform efficiently identifies high-affinity TAA-specific TCRs, including against previously intractable targets. Considering the potential for MHC modularity of this in vitro system, this approach may theoretically enable rapid discovery of therapeutic TCRs based on any designated peptide/MHC-I combination. Citation Format: Chloe S. Wang, Suwen Li, Zhiyuan Mao, Olivia Zhou, Carlos Botero, William Satyadi, Patrick Chang, Sang Pil Yoo, Ho-Chung Chen, Shawn Lopez, Jami McLaughlin, Amélie Montel-Hagen, Owen N. Witte, Gay M. Crooks, Christopher S. Seet. PSC-derived T cells as a novel source of tumor antigen-specific T cell receptors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3604.

Copy number variations across the blood–brain barrier in multiple sclerosis

ObjectiveMultiple sclerosis (MS) is a neuroinflammatory disease where immune cells cross the blood–brain barrier (BBB) into the central nervous system (CNS). What predisposes these immune cells to cross the BBB is still unknown. Here, we examine the possibility that genomic rearrangements could predisposespecific immune cells in the peripheral blood to cross the BBB and form sub‐populations of cells involved in the inflammatory process in the CNS.MethodsWe compared copy number variations in paired peripheral blood mononuclear cells (PBMCs) and cerebrospinal fluid (CSF) cells from MS patients. Thereafter, using next generation sequencing, we studied the T‐cell receptor beta (TRB) locus rearrangements and profiled the αβ T cell repertoire in peripheral CD4+ and CD8+ T cells and in the CSF.ResultsWe identified deletions in the T‐cell receptor alpha/delta (TRA/D), gamma (TRG), and TRB loci in CSF cells compared to PBMCs. Further characterization revealed diversity of the TRB locus which was used to describe the character and clonal expansion of T cells in the CNS. T‐cell repertoire profiling from either side of the BBB concluded that the most frequent clones in the CSF samples are unique to an individual. Furthermore, we observed a difference in the proportion of expanded T‐cell clones when comparing samples from MS patients in relapse and remission with opposite trends in CSF and peripheral blood.InterpretationThis study provides a characterization of the T cells in the CSF and might indicate a role of expanded clones in MS pathogenicity.

Fully Automated Workflows Quantify and Report Key T-Cell and B-Cell Receptor Biomarkers Relevant to Immuno-Oncology and Heme-Oncology Research

BackgroundT-cell and B-cell repertoire analysis is used in oncology research, to understand the etiology of complex disease phenotypes, for the identification of biomarkers predictive of disease burden, outcome, and response to treatment, and for research in diagnosis and recurrence monitoring. Key predictors include secondary and tertiary repertoire features not reported by existing sequencing software solutions. For example, due to ongoing somatic hypermutation in mature B-cell receptors, the underlying sequence of a given clone can accumulate base differences and appear as several distinct clones with smaller frequencies, thereby hampering the ability of analysis software to detect its presence as a single dominant clone with the highest frequency. This has particularly detrimental implications for research in disorders such as follicular lymphoma and may require clonal lineage analysis for proper mitigation. Therefore, to aid the downstream analytics of biomarker identification and the study of complex disease, we developed fully automated analysis solutions that directly compute and report several key features (clonal lineage, amongst several others described below) pertinent to this area of research.ResultsWe developed the Oncomine™ TCR Beta-SR, TCR Gamma-SR, BCR IGH-SR and BCR IGKL-SR workflows on Ion Reporter™ to characterize T-cell (β, γ chains) and B-cell (heavy and light (κ, δ) chains) repertoires. These workflows generate output tables and visualizations for primary repertoire features such as detected clones (viz., unique rearrangements in the receptor DNA sequence), their frequencies, as well as their somatic hypermutation levels in the case of B-cells (Figure 1a & 1b) for clonality assessment and rare clone detection. The software also quantifies and reports several secondary and tertiary repertoire features in a sample, such as clonal diversity, evenness of the clonal population, and B-cell lineage groupings useful in identifying related sub-clones. It includes spectratyping format plots to simultaneously assess the above features as a function of v-gene usage and CDR3 length combinations (Figure 1c & 1d), thereby providing users a complete snapshot of the repertoire, and also the capability to quickly determine CDR3 lengths and V-gene usage of highly expanded or mutated clones. A separate CDR3 lengths histogram is included, as well as a heatmap that depicts the distributions/intensity of Variable-Joining gene combinations (Figure 1e & 1f).Furthermore, the TCR workflows also report (i) convergence frequencies (fraction of clones with different nucleotide sequences, but identical amino acid sequences), and (ii) haplotype grouping for an analyzed sample, based on V-gene allele genotyping and clustering (Figure 1g). In addition, the long read Oncomine™ BCR IGH-LR workflow uniquely reports the isotype class for every detected clone, and includes a visualization of total reads, clones and lineages in the sample represented by isotype (Figure 1h).ConclusionThe Oncomine™ immune repertoire workflows for T-cell and B-cell receptor sequencing were designed to be of high utility in distinct areas of malignancy research, and we expect them to greatly simplify complex downstream analyses. The unique capabilities of the workflows to automatically report secondary and tertiary repertoire features such as (i) clonal lineages for improved dominant clone detection in blood cancers, (ii) TCR clone convergence for prediction of response to immune checkpoint inhibitors [1,2], (iii) TCR haplotype grouping for evaluation of risk factors for autoimmunity and immune-related adverse events [3], and (iv) isotype classification in BCRs for studying pan-cancer immune evasion mechanisms, demonstrate the clear advantages of using these automated workflows over other existing solutions.For research use only.References1) Looney TJ et al. (2020) TCR Convergence in Individuals Treated With Immune Checkpoint Inhibition for Cancer. Front. Immunol. 10:2985.2) Naidus et al. (2021) Early changes in the circulating T cells are associated with clinical outcomes after PD-L1 blockade by durvalumab in advanced NSCLC patients. Cancer Immunology, Immunotherapy 70:2095-21023) Looney TJ et al. (2019) Haplotype Analysis of the T-Cell Receptor Beta (TCRB) Locus by Long-amplicon TCRB Repertoire Sequencing. Journal of Immunotherapy and Precision Oncology. 2 (4): 137-143. [Display omitted] DisclosuresSarda: Thermo Fisher Scientific: Current Employment. Lowman: Thermo Fisher Scientific: Current Employment. Toro: Thermo Fisher Scientific: Current Employment. Pickle: Thermo Fisher Scientific: Current Employment. Looney: Thermo Fisher Scientific: Ended employment in the past 24 months; Singular Genomics: Current Employment. Hyland: Thermo Fisher Scientific: Current Employment.

Performance of Next Generation Sequencing for Minimal Residual Disease Detection for Pediatric Patients with Acute Lymphoblastic Leukemia: Results from the Prospective Clinical Trial DFCI 16-001

Performance of Next Generation Sequencing for Minimal Residual Disease Detection for Pediatric Patients with Acute Lymphoblastic Leukemia: Results from the Prospective Clinical Trial DFCI 16-001

Novel clonality assays for T cell lymphoma in cats targeting the T cell receptor beta, T cell receptor delta, and T cell receptor gamma loci.

BackgroundT cell clonality assays in veterinary medicine currently target only the T cell receptor gamma (TRG) locus. Existing assays have suboptimal sensitivity because of insufficient primer coverage of all possible rearrangements.ObjectiveDevelop higher sensitivity clonality assays targeting the TRG, delta (TRD), and beta (TRB) loci in cats.AnimalsCats with histopathologically confirmed lymphoma (n = 89), non‐lymphoma (n = 35), and possible hepatic small cell lymphoma (n = 31).MethodsMolecular clonality assay development utilizing our recently reported topology and expressed repertoire data of the T cell receptor loci in cats. Determination of clonality status of lymphoma, non lymphoma, and possible hepatic small cell lymphoma samples, and calculation of assay sensitivity and specificity.ResultsThe new multiplex TRG assay yielded the highest sensitivity (95.5%). All assays yielded 100% specificity except for the new multiplex TRG assay (97.3%). The combination of the new TRG and TRB assays yielded sensitivity of 98.9% and specificity of 97.0%. The new TRG assay detected clonality in 17/31 possible small cell lymphoma livers, whereas an existing TRG assay detected clonality in 6/31 livers.Conclusions and Clinical ImportanceThe assessment of multiple T cell loci compensates for the potential shortcomings of individual assays. Using a combination of molecular clonality assays will increase the overall sensitivity for the diagnosis of T‐cell lymphoma in cats, especially intestinal, and hepatic small cell lymphoma. Hepatic small cell lymphomas detected by the new TRG assay utilized rarely expressed V and J genes not recognized by previous assays, likely indicating unique biology of hepatic small cell lymphoma in cats.

Hist-O-06 - Image-guided lymph node core-needle biopsy predicts survival in mycosis fungoides and Sézary syndrome

<h3>Background:</h3> The prognosis of Sézary syndrome (SS) and mycosis fungoides (MF) depends on lymph node (LN) involvement. The usefulness of LN image-guided core-needle biopsies (CNBs), instead of surgical sampling, has been poorly evaluated. <h3>Objectives:</h3> To determine the prognostic value of LN CNB in MF/SS. <h3>Methods:</h3> A retrospective search was conducted to identify all LN biopsy specimens of MF/SS between 2008 and 2019. Biopsies were staged according to the International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer (ISCL/EORTC) criteria. We performed immunolabelling and determined the tumour clone frequency (TCF) by high-throughput sequencing of the T-cell receptor beta locus. <h3>Results:</h3> We included 119 consecutive biopsies from 100 patients, 45 with MF and 55 with SS. N1, N2 and N3 stages were diagnosed in 34 (29%), 26 (22%) and 59 (49%) cases, respectively. The TCF, Ki67 index, and percentage of cells positive for thymocyte selection-associated high mobility group box protein (TOX), programmed cell death protein 1 (PD1), killer cell immunoglobulin-like receptor 3DL2 (KIR3DL2) and cluster of differentiation (CD)30 were all positively correlated with the N stage. Median overall survival (OS) for N1/N2 vs. N3 patients was 42 months (range 26–not reached) vs. 14 months (range 5–30), respectively (p<0.001). In univariate analyses, an age >75 years, LN short-axis diameter >15 mm, N3 stage, presence of large-cell transformation, TOX >60%, PD1 >25%, Ki67 >30%, KIR3DL2 >15%, CD30 >10% and TCF >25% were identified as adverse prognostic factors. In multivariate analyses, only an age >75 years and Ki67 index >30% were associated with reduced OS. We developed a new prognostic index associating the N stage and the Ki67 index, which better discriminates N3 patients with poor prognosis. <h3>Conclusions:</h3> CNB allows an objective assessment of the LN involvement in MF/SS, relevant for staging and prognosis.

T cell receptor beta locus sequencing early post-allogeneic stem cell transplant identifies patients at risk of initial and recurrent cytomegalovirus infection.

Identification of patients at risk of initial & recurrent cytomegalovirus (CMV) reactivation following allogeneic stem cell transplant (alloSCT) may help guide prophylactic strategies. T-cell receptor beta (TRB) deep sequencing was used to identify and enumerate the T-cell repertoire harbouring TRB sequences with annotated specificity to CMV (pubCMVrep), as well as the overall T-cell receptor (TCR) repertoire diversity at day +30 & day +60 post-alloSCT for 65 patients. T-cells harbouring TRB sequences with annotated specificity for CMV were identifiable in all patients. 56% of patients required CMV treatment and 23% of the cohort developed recurrent CMV. PubCMVrep size at day +30 was not associated with reactivation, however amongst patients with antecedent CMV viremia a low day +60 pubCMVrep was associated with a greater incidence of recurrent CMV (75% vs. 21%, HR 6.16, 95% CI 1.29-29.40, P = 0.0008). Moreover, patients with high pubCMVrep only developed recurrent CMV in the setting of GVHD. Low TCR diversity at day +30 was associated with a greater incidence of initial CMV reactivation (71% vs. 22%, HR 5.39, 95% CI 1.70-17.09, p = 0.0002). pubCMVrep and TCR diversity are promising biomarkers to identify patients at risk of initial & recurrent CMV who may benefit from novel prophylactic strategies.

Discovery and fine-mapping of kidney function loci in first genome-wide association study in Africans.

Genome-wide association studies (GWAS) of kidney function have uncovered hundreds of loci, primarily in populations of European ancestry. We have undertaken the first continental African GWAS of estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We conducted GWAS of eGFR in 3288 East Africans from the Uganda General Population Cohort (GPC) and replicated in 8224 African Americans from the Women’s Health Initiative. Loci attaining genome-wide significant evidence for association (P < 5 × 10−8) were followed up with Bayesian fine-mapping to localize potential causal variants. The predictive power of a genetic risk score (GRS) constructed from previously reported trans-ancestry eGFR lead single nucleotide polymorphism (SNPs) was evaluated in the Uganda GPC. We identified and validated two eGFR loci. At the glycine amidinotransferase (GATM) locus, the association signal (lead SNP rs2433603, P = 1.0 × 10−8) in the Uganda GPC GWAS was distinct from previously reported signals at this locus. At the haemoglobin beta (HBB) locus, the association signal (lead SNP rs141845179, P = 3.0 × 10−8) has been previously reported. The lead SNP at the HBB locus accounted for 88% of the posterior probability of causality after fine-mapping, but did not colocalise with kidney expression quantitative trait loci. The trans-ancestry GRS of eGFR was not significantly predictive into the Ugandan population. In the first GWAS of eGFR in continental Africa, we validated two previously reported loci at GATM and HBB. At the GATM locus, the association signal was distinct from that previously reported. These results demonstrate the value of performing GWAS in continental Africans, providing a rich genomic resource to larger consortia for further discovery and fine-mapping. The study emphasizes that additional large-scale efforts in Africa are warranted to gain further insight into the genetic architecture of CKD.

MYB rearrangements and over-expression in T-cell acute lymphoblastic leukemia.

We investigated MYB rearrangements (MYB-R) and the levels of MYB expression, in 331 pediatric and adult patients with T-cell acute lymphoblastic leukemia (T-ALL). MYB-R were detected in 17 cases and consisted of MYB tandem duplication (tdup) (= 14) or T cell receptor beta locus (TRB)-MYB (= 3). As previously reported, TRB-MYB was found only in children (1.6%) while MYB tdup occurred in both age groups, although it was slightly more frequent in children (5.2% vs 2.8%). Shared features of MYB-R T-ALL were a non-early T-cell precursor (ETP) phenotype, a high incidence of NOTCH1/FBXW7 mutations (81%) and CDKN2AB deletions (70.5%). Moreover, they mainly belonged to HOXA (=8), NKX2-1/2-2/TLX1 (=4), and TLX3 (=3) homeobox-related subgroups. Overall, MYB-R cases had significantly higher levels of MYB expression than MYB wild type (MYB-wt) cases, although high levels of MYB were detected in ~ 30% of MYB-wt T-ALL. Consistent with the transcriptional regulatory networks, cases with high MYB expression were significantly enriched within the TAL/LMO subgroup (P = .017). Interestingly, analysis of paired diagnosis/remission samples demonstrated that a high MYB expression was restricted to the leukemic clone. Our study has indicated that different mechanisms underlie MYB deregulation in 30%-40% of T-ALL and highlighted that, MYB has potential as predictive/prognostic marker and/or target for tailored therapy.