Characteristics of white blood cell count in acute lymphoblastic leukemia : A COST LEGEND phenotype-genotype study

Background White blood cell count (WBC) as a measure of extramedullary leukemic cell survival is a well-known prognostic factor in acute lymphoblastic leukemia (ALL), but its biology, including impact of host genome variants, is poorly understood. Methods We included patients treated with the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL-2008 protocol (N = 2347, 72% were genotyped by Illumina Omni2.5exome-8-Bead chip) aged 1-45 years, diagnosed with B-cell precursor (BCP-) or T-cell ALL (T-ALL) to investigate the variation in WBC. Spline functions of WBC were fitted correcting for association with age across ALL subgroups of immunophenotypes and karyotypes. The residuals between spline WBC and actual WBC were used to identify WBC-associated germline genetic variants in a genome-wide association study (GWAS) while adjusting for age and ALL subtype associations. Results We observed an overall inverse correlation between age and WBC, which was stronger for the selected patient subgroups of immunophenotype and karyotypes (rho(BCP-ALL )= -.17, rho(T-ALL )= -.19; p < 3 x 10(-4)). Spline functions fitted to age, immunophenotype, and karyotype explained WBC variation better than age alone (rho = .43, p << 2 x 10(-6)). However, when the spline-adjusted WBC residuals were used as phenotype, no GWAS significant associations were found. Based on available annotation, the top 50 genetic variants suggested effects on signal transduction, translation initiation, cell development, and proliferation. Conclusion These results indicate that host genome variants do not strongly influence WBC across ALL subsets, and future studies of why some patients are more prone to hyperleukocytosis should be performed within specific ALL subsets that apply more complex analyses to capture potential germline variant interactions and impact on WBC.Peer reviewe

Immunotherapeutic effects of intratumoral nanoplexed poly I:C

Poly I:C is a powerful immune adjuvant as a result of its agonist activities on TLR-3, MDA5 and RIG-I. BO-112 is a nanoplexed formulation of Poly I:C complexed with polyethylenimine that causes tumor cell apoptosis showing immunogenic cell death features and which upon intratumoral release results in more prominent tumor infiltration by T lymphocytes. Intratumoral treatment with BO-112 of subcutaneous tumors derived from MC38, 4 T1 and B16- F10 leads to remarkable local disease control dependent on type-1 interferon and gamma-interferon. Some degree of control of non-injected tumor lesions following BO-112 intratumoral treatment was found in mice bearing bilateral B16-OVA melanomas, an activity which was enhanced with co-treatment with systemic anti-CD137 and anti-PD-L1 mAbs. More abundant CD8+ T lymphocytes were found in B16-OVA tumor-draining lymph nodes and in the tumor microenvironment following intratumoral BO-112 treatment, with enhanced numbers of tumor antigen-specific cytotoxic T lymphocytes. Genome-wide transcriptome analyses of injected tumor lesions were consistent with a marked upregulation of the type-I interferon pathway. Inspired by these data, intratumorally delivered BO-112 is being tested in cancer patients (NCT02828098)

Genetics and Epigenetics in Complex Diseases

Many of the most common diseases are influenced by a combination of multiple factors, which include environmental effectors, as well as genetic and epigenetic variations [...

New insights into methotrexate accumulation in leukemia cells in vivo

Measuring the amount of methotrexate polyglutamates (MTXPG) in leukemia cells after high-dose methotrexate (HDMTX) revealed that molecular subtype and lineage of acute lymphoblastic leukemia (ALL), the ratio of expression of folate influx and efflux transporters, methotrexate (MTX) infusion time, folylpolyglutamate synthase mRNA expression, and MTX systemic clearance explain 42% of the variation in active MTXPGs accumulation in ALL cells in vivo, providing insights into mechanisms underlying interpatient differences in the antileukemic effects of HDMTX

Systematic Review of the Potential of MicroRNAs in Diffuse Large B Cell Lymphoma

Diffuse large B cell lymphoma (DLBCL) is the most common subtype of invasive non-Hodgkin&#8217;s lymphoma (NHL). DLBCL presents with variable backgrounds, which results in heterogeneous outcomes among patients. Although new tools have been developed for the classification and management of patients, 40% of them still have primary refractory disease or relapse. In addition, multiple factors regarding the pathogenesis of this disease remain unclear and identification of novel biomarkers is needed. In this context, recent investigations point to microRNAs as useful biomarkers in cancer. The aim of this systematic review was to provide new insight into the role of miRNAs in the diagnosis, classification, treatment response and prognosis of DLBCL patients. We used the following terms in PubMed&#8222; ((&#8216;Non-coding RNA&#8217;) OR (&#8216;microRNA&#8217; OR &#8216;miRNA&#8217; OR &#8216;miR&#8217;) OR (&#8216;exosome&#8217;) OR (&#8216;extracellular vesicle&#8217;) OR (&#8216;secretome&#8217;)) AND (&#8216;Diffuse large B cell lymphoma&#8217; OR &#8216;DLBCL&#8217;)&#8222; to search for studies evaluating miRNAs as a diagnosis, subtype, treatment response or prognosis biomarkers in primary DLBCL in human patient populations. As a result, the analysis was restricted to the role of miRNAs in tumor tissue and we did not consider circulating miRNAs. A total of thirty-six studies met the inclusion criteria. Among them, twenty-one were classified in the diagnosis category, twenty in classification, five in treatment response and nineteen in prognosis. In this review, we have identified miR-155-5p and miR-21-5p as miRNAs of potential utility for diagnosis, while miR-155-5p and miR-221-3p could be useful for classification. Further studies are needed to exploit the potential of this field

Systematic Review of Pharmacogenetic Factors That Influence High-Dose Methotrexate Pharmacokinetics in Pediatric Malignancies

SIMPLE SUMMARY: High-dose methotrexate is commonly used to treat several types of cancer. While effective, elimination of high-dose methotrexate from the body is highly variable and delayed elimination can lead to serious and sometime life-threatening adverse events. There have been many clinical studies to better understand how genetics influence the variability in methotrexate elimination, mostly through candidate gene studies and three genome-wide association studies. Unfortunately, there are conflicting results and some studies lack the appropriate replication and validation needed to confirm their effects on methotrexate elimination. Therefore, the purpose of this systematic review was to summarize all of the germline pharmacogenetic association studies of genetic associations influencing high-dose methotrexate elimination in children with cancer. ABSTRACT: Methotrexate (MTX) is a mainstay therapeutic agent administered at high doses for the treatment of pediatric and adult malignancies, such as acute lymphoblastic leukemia, osteosarcoma, and lymphoma. Despite the vast evidence for clinical efficacy, high-dose MTX displays significant inter-individual pharmacokinetic variability. Delayed MTX clearance can lead to prolonged, elevated exposure, causing increased risks for nephrotoxicity, mucositis, seizures, and neutropenia. Numerous pharmacogenetic studies have investigated the effects of several genes and polymorphisms on MTX clearance in an attempt to better understand the pharmacokinetic variability and improve patient outcomes. To date, several genes and polymorphisms that affect MTX clearance have been identified. However, evidence for select genes have conflicting results or lack the necessary replication and validation needed to confirm their effects on MTX clearance. Therefore, we performed a systematic review to identify and then summarize the pharmacogenetic factors that influence high-dose MTX pharmacokinetics in pediatric malignancies. Using the PRISMA guidelines, we analyzed 58 articles and 24 different genes that were associated with transporter pharmacology or the folate transport pathway. We conclude that there is only one gene that reliably demonstrates an effect on MTX pharmacokinetics: SLCO1B1

Genetic Variants in MiRNA Processing Genes and Pre-MiRNAs Are Associated with the Risk of Chronic Lymphocytic Leukemia

<div><p>Genome wide association studies (GWAS) have identified several low-penetrance susceptibility alleles in chronic lymphocytic leukemia (CLL). Nevertheless, these studies scarcely study regions that are implicated in non-coding molecules such as microRNAs (miRNAs). Abnormalities in miRNAs, as altered expression patterns and mutations, have been described in CLL, suggesting their implication in the development of the disease. Genetic variations in miRNAs can affect levels of miRNA expression if present in pre-miRNAs and in miRNA biogenesis genes or alter miRNA function if present in both target mRNA and miRNA sequences. Therefore, the present study aimed to evaluate whether polymorphisms in pre-miRNAs, and/or miRNA processing genes contribute to predisposition for CLL. A total of 91 SNPs in 107 CLL patients and 350 cancer-free controls were successfully analyzed using TaqMan Open Array technology. We found nine statistically significant associations with CLL risk after FDR correction, seven in miRNA processing genes (rs3805500 and rs6877842 in <i>DROSHA</i>, rs1057035 in <i>DICER1</i>, rs17676986 in <i>SND1</i>, rs9611280 in <i>TNRC6B</i>, rs784567 in <i>TRBP</i> and rs11866002 in <i>CNOT1</i>) and two in pre-miRNAs (rs11614913 in miR196a2 and rs2114358 in miR1206). These findings suggest that polymorphisms in genes involved in miRNAs biogenesis pathway as well as in pre-miRNAs contribute to the risk of CLL. Large-scale studies are needed to validate the current findings.</p></div

Secondary structures of the miRNAs showing significant SNPs.

<p>(A) miR196a2 and (B) miR1206, predicted by the RNAfold tool.</p