Circulating microbial content in myeloid malignancy patients is associated with disease subtypes and patient outcomes

Although recent work has described the microbiome in solid tumors, microbial content in hematological malignancies is not well-characterized. Here we analyze existing deep DNA sequence data from the blood and bone marrow of 1870 patients with myeloid malignancies, along with healthy controls, for bacterial, fungal, and viral content. After strict quality filtering, we find evidence for dysbiosis in disease cases, and distinct microbial signatures among disease subtypes. We also find that microbial content is associated with host gene mutations and with myeloblast cell percentages. In patients with low-risk myelodysplastic syndrome, we provide evidence that Epstein-Barr virus status refines risk stratification into more precise categories than the current standard. Motivated by these observations, we construct machine-learning classifiers that can discriminate among disease subtypes based solely on bacterial content. Our study highlights the association between the circulating microbiome and patient outcome, and its relationship with disease subtype

Clinical and basic implications of dynamic T cell receptor clonotyping in hematopoietic cell transplantation

TCR repertoire diversification constitutes a foundation for successful immune reconstitution after allogeneic hematopoietic cell transplantation (allo-HCT). Deep TCR V beta sequencing of 135 serial specimens from a cohort of 35 allo-HCT recipients/donors was performed to dissect posttransplant TCR architecture and dynamics. Paired analysis of clonotypic repertoires showed a minimal overlap with donor expansions. Rarefied and hyperexpanded clonotypic patterns were hallmarks of T cell reconstitution and influenced clinical outcomes. Donor and pretransplant TCR diversity as well as divergence of class I human leukocyte antigen genotypes were major predictors of recipient TCR repertoire recovery. Complementary determining region 3-based specificity spectrum analysis indicated a predominant expansion of pathogen- and tumor-associated clonotypes in the late post-allo-HCT phase, while autoreactive clones were more expanded in the case of graft-versus-host disease occurrence. These findings shed light on post-allo-HCT adaptive immune reconstitution processes and possibly help in tracking alloreactive responses

The similarity of class II HLA genotypes defines patterns of autoreactivity in idiopathic bone marrow failure disorders

Abstract Idiopathic aplastic anemia (IAA) is a rare autoimmune bone marrow failure (BMF) disorder initiated by a human leukocyte antigen (HLA)-restricted T-cell response to unknown antigens. As in other autoimmune disorders, the predilection for certain HLA profiles seems to represent an etiologic factor; however, the structure-function patterns involved in the self-presentation in this disease remain unclear. Herein, we analyzed the molecular landscape of HLA complexes of a cohort of 300 IAA patients and almost 3000 healthy and disease controls by deeply dissecting their genotypic configurations, functional divergence, self-antigen binding capabilities, and T-cell receptor (TCR) repertoire specificities. Specifically, analysis of the evolutionary divergence of HLA genotypes (HED) showed that IAA patients carried class II HLA molecules whose antigen-binding sites were characterized by a high level of structural homology, only partially explained by specific risk allele profiles. This pattern implies reduced HLA binding capabilities, confirmed by binding analysis of hematopoietic stem cell (HSC)-derived self-peptides. IAA phenotype was associated with the enrichment in a few amino acids at specific positions within the peptide-binding groove of DRB1 molecules, affecting the interface HLA-antigen-TCR β and potentially constituting the basis of T-cell dysfunction and autoreactivity. When analyzing associations with clinical outcomes, low HED was associated with risk of malignant progression and worse survival, underlying reduced tumor surveillance in clearing potential neoantigens derived from mechanisms of clonal hematopoiesis. Our data shed light on the immunogenetic risk associated with IAA etiology and clonal evolution and on general pathophysiological mechanisms potentially involved in other autoimmune disorders.Peer reviewe

TET2 mutations as a part of DNA dioxygenase deficiency in myelodysplastic syndromes

Decrease in DNA dioxygenase activity generated by TET2 gene family is crucial in myelodysplastic syndromes (MDS). The general downregulation of 5-hydroxymethylcytosine (5-hmC) argues for a role of DNA demethylation in MDS beyond TET2 mutations, which albeit frequent, do not convey any prognostic significance. We investigated TETs expression to identify factors which can modulate the impact of mutations and thus 5-hmC levels on clinical phenotypes and prognosis of MDS patients. DNA/RNA-sequencing and 5-hmC data were collected from 1665 patients with MDS and 91 controls. Irrespective of mutations, a significant fraction of MDS patients exhibited lower TET2 expression, whereas 5-hmC levels were not uniformly decreased. In searching for factors explaining compensatory mechanisms, we discovered that TET3 was upregulated in MDS and inversely correlated with TET2 expression in wild type cases. Although TET2 was reduced across all age groups, TET3 levels were increased in a likely feedback mechanism induced by TET2 dysfunction. This inverse relationship of TET2 and TET3 expression also corresponded to the expression of L-2-hydroxyglutarate dehydrogenase, involved in agonist/antagonist substrate metabolism. Importantly, elevated TET3 levels influ-enced the clinical phenotype of TET2 deficiency whereby the lack of compensation by TET3 (low TET3 expression) was associated with poor outcomes of TET2 mutant carriers

A Machine Learning Model of Response to Hypomethylating Agents in Myelodysplastic Syndromes

Hypomethylating agents (HMA) prolong survival and improve cytopenias in individuals with higher-risk myelodysplastic syndrome (MDS). Only 30-40% of patients, however, respond to HMAs, and responses may not occur for more than 6 months after HMA initiation. We developed a model to more rapidly assess HMA response by analyzing early changes in patients’ blood counts. Three institutions’ data were used to develop a model that assessed patients’ response to therapy 90 days after the initiation using serial blood counts. The model was developed with a training cohort of 424 patients from2 institutions and validated on an independent cohort of 90 patients. The final model achieved an area under the receiver operating characteristic curve (AUROC) of 0.79 in the train/test group and 0.84 in the validation group. The model provides cohort-wide and individual- level explanations for model predictions, and model certainty can be interrogated to gauge the reliability of a given prediction

Constraints on Higgs boson properties using WW∗(→ eνμν) jj production in 36.1fb-1 of √s=13 TeV pp collisions with the ATLAS detector

This article presents the results of two studies of Higgs boson properties using the WW∗(→ eνμν) jj final state, based on a dataset corresponding to 36.1 fb - 1 of s=13 TeV proton–proton collisions recorded by the ATLAS experiment at the Large Hadron Collider. The first study targets Higgs boson production via gluon–gluon fusion and constrains the CP properties of the effective Higgs–gluon interaction. Using angular distributions and the overall rate, a value of tan (α) = 0.0 ± 0.4 (stat.) ± 0.3 (syst.) is obtained for the tangent of the mixing angle for CP-even and CP-odd contributions. The second study exploits the vector-boson fusion production mechanism to probe the Higgs boson couplings to longitudinally and transversely polarised W and Z bosons in both the production and the decay of the Higgs boson; these couplings have not been directly constrained previously. The polarisation-dependent coupling-strength scale factors are defined as the ratios of the measured polarisation-dependent coupling strengths to those predicted by the Standard Model, and are determined using rate and kinematic information to be aL=0.91-0.18+0.10(stat.)-0.17+0.09(syst.) and aT= 1.2 ± 0.4 (stat.)-0.3+0.2(syst.). These coupling strengths are translated into pseudo-observables, resulting in κVV=0.91-0.18+0.10(stat.)-0.17+0.09(syst.) and ϵVV=0.13-0.20+0.28 (stat.)-0.10+0.08(syst.). All results are consistent with the Standard Model predictions

Measurement of the energy asymmetry in tt¯ j production at 13 TeV with the ATLAS experiment and interpretation in the SMEFT framework

A measurement of the energy asymmetry in jet-associated top-quark pair production is presented using 139fb-1 of data collected by the ATLAS detector at the Large Hadron Collider during pp collisions at s=13TeV. The observable measures the different probability of top and antitop quarks to have the higher energy as a function of the jet scattering angle with respect to the beam axis. The energy asymmetry is measured in the semileptonic tt¯ decay channel, and the hadronically decaying top quark must have transverse momentum above 350GeV. The results are corrected for detector effects to particle level in three bins of the scattering angle of the associated jet. The measurement agrees with the SM prediction at next-to-leading-order accuracy in quantum chromodynamics in all three bins. In the bin with the largest expected asymmetry, where the jet is emitted perpendicular to the beam, the energy asymmetry is measured to be - 0.043 ± 0.020 , in agreement with the SM prediction of - 0.037 ± 0.003. Interpreting this result in the framework of the Standard Model effective field theory (SMEFT), it is shown that the energy asymmetry is sensitive to the top-quark chirality in four-quark operators and is therefore a valuable new observable in global SMEFT fits