Mannose binding lectin (MBL) is an important component of the innate immune response. Low producing MBL alleles are associated with an increased risk of infection, especially when adaptive immunity ...is already compromized. We investigated the role of MBL polymorphism in common variable immunodeficiency (CVID), a disease of unknown aetiology characterized by defective humoral immunity, recurrent infections and highly variable clinical phenotype. Six biallelic single nucleotide polymorphisms in the MBL promoter and coding region (– 550, − 221, + 4, codons 52, 54 and 57) were haplotyped using a novel PCR‐SSP method in 163 CVID patients and 100 controls. Low producing coding alleles and promoter haplotypes were associated with early age of disease onset. The mean age of disease onset was 14.5 years in patients with low producing MBL coding alleles, compared with 25 years in patients with wild type coding regions (t‐test P = 0.002). Mean age of onset in patients with the low producing LXPA haplotype was 6.8 years, compared with 29.3 years for the HYPA haplotype (P = 0.003). The MBL + 4 Q allele was associated with autoimmune disease (P = 0.003, OR 4.4). These results suggest that MBL deficiency compounds the antibody deficiency in CVID, and reinforces the ostensible role of MBL in innate immunity. MBL deficiency may also facilitate the development of autoimmune disease in CVID.
Myelodysplastic syndromes (MDS) are uncommon in children and have a poor prognosis. In contrast to adult MDS, little is known about the genomic landscape of pediatric MDS. Here, we describe the ...somatic and germline changes of pediatric MDS using whole exome sequencing, targeted amplicon sequencing, and/or RNA-sequencing of 46 pediatric primary MDS patients. Our data show that, in contrast to adult MDS, Ras/MAPK pathway mutations are common in pediatric MDS (45% of primary cohort), while mutations in RNA splicing genes are rare (2% of primary cohort). Surprisingly, germline variants in SAMD9 or SAMD9L were present in 17% of primary MDS patients, and these variants were routinely lost in the tumor cells by chromosomal deletions (e.g., monosomy 7) or copy number neutral loss of heterozygosity (CN-LOH). Our data confirm that adult and pediatric MDS are separate diseases with disparate mechanisms, and that SAMD9/SAMD9L mutations represent a new class of MDS predisposition.
Life-threatening complications such as graft versus host disease and infection remain major barriers to the success of allogeneic hemopoietic stem cell transplantation (SCT). While pretransplantation ...conditioning and posttransplantation immunosuppression are important risk factors for infection, the reasons that similarly immunosuppressed transplant recipients show marked variation in frequency of infection after allogeneic SCT are unclear. Mannose-binding lectin (MBL) deficiency is a risk factor for infection in other situations where immunity is compromised. We investigated associations betweenMBL2 gene polymorphisms and risk of major infection following allogeneic SCT. Ninety-seven related allogeneic donor-recipient pairs were studied. Clinical data including survival, days of fever, graft versus host disease incidence and severity, and infection were collected by case note review. Five single-nucleotide polymorphisms in the MBL2 gene were genotyped using the polymerase chain reaction and sequence-specific primers.MBL2 coding mutations were associated with an increased risk of major infection following transplantation. This association was seen for donor (P = .002, odds ratio OR 4.1) and recipient (P = .04, OR 2.6) MBL2 genotype.MBL2 promoter variants were also associated with major infection. The high-producing haplotype HYA was associated with a markedly reduced risk of infection (recipient HYA P = .0001, OR 0.16; donor HYA P = .001, OR 0.23). Donor MBL2 coding mutations and recipientHYA haplotype were independently associated with infection in multivariate analysis. These results suggest that MBL2genotype influences the risk of infection following allogeneic SCT and that both donor and recipient MBL2 genotype are important. These findings raise the possibility that MBL replacement therapy may be useful following transplantation.
Summary Background About a fifth of children with acute T-lymphoblastic leukaemia (T-ALL) succumb to the disease, suggesting an unrecognised biological heterogeneity that might contribute to drug ...resistance. We postulated that T-ALL originating from early T-cell precursors (ETPs), a recently defined subset of thymocytes that retain stem-cell-like features, would respond poorly to lymphoid-cell-directed therapy. We studied leukaemic cells, collected at diagnosis, to identify cases with ETP features and determine their clinical outcome. Methods Leukaemic cells from 239 patients with T-ALL enrolled at St Jude Children's Research Hospital (n=139) and in the Italian national study Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) ALL-2000 (n=100) were assessed by gene-expression profiling, flow cytometry, and single nucleotide polymorphism array analysis. Probabilities of survival and treatment failure were calculated for subgroups considered to have ETP-ALL or typical T-ALL. Findings 30 patients (12·6%) had leukaemic lymphoblasts with an ETP-related gene-expression signature or its associated distinctive immunophenotype (CD1a− , CD8− , CD5weak with stem-cell or myeloid markers). Cases of ETP-ALL showed increased genomic instability, in terms of number and size of gene lesions, compared with those with typical T-ALL. Patients with this form of leukaemia had high risk of remission failure or haematological relapse (72% 95% CI 40–100 at 10 years vs 10% 4–16 at 10 years for patients with typical T-ALL treated at St Jude Children's Research Hospital; and 57% 25–89 at 2 years vs 14% 6–22 at 2 years for patients treated in the AIEOP trial). Interpretation ETP-ALL is a distinct, previously unrecognised, pathobiological entity that confers a poor prognosis with use of standard intensive chemotherapy. Its early recognition, by use of the gene expression and immunophenotypic criteria outlined here, is essential for the development of an effective clinical management strategy. Funding US National Cancer Institute, Cariplo Foundation, Citta della Speranza Foundation, Italian Association for Cancer Research (AIRC), Italian Ministry for University and Research, and American Lebanese Syrian Associated Charities (ALSAC).
The increasing use of mass cytometry for analyzing clinical samples offers the possibility to perform comparative analyses across public datasets. However, challenges in batch normalization and data ...integration limit the comparison of datasets not intended to be analyzed together. Here, we present a data integration strategy, CytofIn, using generalized anchors to integrate mass cytometry datasets from the public domain. We show that low-variance controls, such as healthy samples and stable channels, are inherently homogeneous, robust against stimulation, and can serve as generalized anchors for batch correction. Single-cell quantification comparing mass cytometry data from 989 leukemia files pre- and post normalization with CytofIn demonstrates effective batch correction while recapitulating the gold-standard bead normalization. CytofIn integration of public cancer datasets enabled the comparison of immune features across histologies and treatments. We demonstrate the ability to integrate public datasets without necessitating identical control samples or bead standards for fast and robust analysis using CytofIn.
Adhesion molecule polymorphisms and the development of chronic renal allograft failure.
Chronic allograft failure (CAF) is a major cause of late graft loss in renal transplantation. Up-regulation of ...adhesion molecules has been demonstrated in renal allograft biopsies during both acute and chronic rejection, and these molecules are known to regulate leukocyte migration into the graft.
A single-center retrospective study was performed between 1985 and 1996 on renal transplant recipients who developed CAF. Genotyping was performed for five polymorphisms in intercellular adhesion molecule-1 (ICAM-1), E-selectin, and L-selectin. Frequency data for the polymorphisms in the CAF group (N = 62) and their matched donors, where available (N = 33), were compared with a group of recipients with graft survival of more than 10years (N = 110) and a group of United Kingdom (UK) controls (N = 101).
A variant allele in exon 4 of ICAM-1 (R241) was more common in the CAF recipients compared with both long-term survivors and UK controls (19.4 vs. 10.0 and 9.4%, P = 0.015 and 0.025). In addition, stratification by time to graft failure caused by CAF revealed more rapid failure in the presence of another ICAM-1 variant in the recipient (E469) in exon 6 (P = 0.033).
ICAM-1 polymorphisms may represent a predetermined genetic risk factor for CAF. The polymorphism in exon 4 is in the Mac-1 binding site, and that in exon 6 is in the fifth immunoglobulin-like domain. Potential mechanisms of action of ICAM-1 variants in CAF include an alteration of activity as an adhesion molecule, altered costimulation, or a minor histocompatibility antigen.
CRLF2 rearrangements, JAK1/2 point mutations, and JAK2 fusion genes have been identified in Philadelphia chromosome (Ph)–like acute lymphoblastic leukemia (ALL), a recently described subtype of ...pediatric high-risk B-precursor ALL (B-ALL) which exhibits a gene expression profile similar to Ph-positive ALL and has a poor prognosis. Hyperactive JAK/STAT and PI3K/mammalian target of rapamycin (mTOR) signaling is common in this high-risk subset. We, therefore, investigated the efficacy of the JAK inhibitor ruxolitinib and the mTOR inhibitor rapamycin in xenograft models of 8 pediatric B-ALL cases with and without CRLF2 and JAK genomic lesions. Ruxolitinib treatment yielded significantly lower peripheral blast counts compared with vehicle (P < .05) in 6 of 8 human leukemia xenografts and lower splenic blast counts (P < .05) in 8 of 8 samples. Enhanced responses to ruxolitinib were observed in samples harboring JAK-activating lesions and higher levels of STAT5 phosphorylation. Rapamycin controlled leukemia burden in all 8 B-ALL samples. Survival analysis of 2 representative B-ALL xenografts demonstrated prolonged survival with rapamycin treatment compared with vehicle (P < .01). These data demonstrate preclinical in vivo efficacy of ruxolitinib and rapamycin in this high-risk B-ALL subtype, for which novel treatments are urgently needed, and highlight the therapeutic potential of targeted kinase inhibition in Ph-like ALL.
Retrospective studies have suggested that older adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) have better survival rates when treated using a pediatric ALL regimen ...administered by pediatric treatment teams. To address the feasibility and efficacy of using a pediatric treatment regimen for AYA patients with newly diagnosed ALL administered by adult treatment teams, we performed a prospective study, CALGB 10403, with doses and schedule identical to those in the Children's Oncology Group study AALL0232. From 2007 to 2012, 318 patients were enrolled; 295 were eligible and evaluable for response. Median age was 24 years (range, 17-39 years). Use of the pediatric regimen was safe; overall treatment-related mortality was 3%, and there were only 2 postremission deaths. Median event-free survival (EFS) was 78.1 months (95% confidence interval CI, 41.8 to not reached), more than double the historical control of 30 months (95% CI, 22-38 months); 3-year EFS was 59% (95% CI, 54%-65%). Median overall survival (OS) was not reached. Estimated 3-year OS was 73% (95% CI, 68%-78%). Pretreatment risk factors associated with worse treatment outcomes included obesity and presence of the Philadelphia-like gene expression signature. Use of a pediatric regimen for AYAs with ALL up to age 40 years was feasible and effective, resulting in improved survival rates compared with historical controls. CALGB 10403 can be considered a new treatment standard upon which to build for improving survival for AYAs with ALL. This trial was registered at www.clinicaltrials.gov as #NCT00558519.
•Using an intensive pediatric regimen for AYAs with ALL is feasible.•High rates of EFS and OS were seen compared with historical controls.
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Background: Fas mediated apoptosis may be important in the pathogenesis of primary Sjögren’s syndrome (pSS). Objective: To examine genetic variation in the promoter region of the Fas gene in pSS. ...Methods: Two single nucleotide polymorphisms at positions −1377(G/A) and −670(G/A) in the Fas gene promoter were genotyped by PCRSSP in 101 patients with pSS and 108 Caucasoid controls. Results: No significant differences in allele or genotype frequencies were detected between the patients with pSS and controls. However, significant associations were observed with Ro/La autoantibody negative patients, who display milder and later onset disease. The −670A allele was more frequent in Ro/La autoantibody negative patients than in Ro/La autoantibody positive patients (p = 0.04). Conclusion: This study does not confirm an earlier report of an association between pSS and the Fas promoter −670G allele. However, the results suggest that genetically determined variability in Fas expression may modulate Ro/La autoantibody responses in patients with pSS.
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