Risk Of Acute Lymphoblastic Leukemia Research Articles

Outdoor artificial light at night, air pollution, and risk of childhood acute lymphoblastic leukemia in the California Linkage Study of Early-Onset Cancers

Acute lymphoblastic leukemia (ALL) is the most common type of cancer in children (age 0–14 years); however, the etiology remains incompletely understood. Several environmental exposures have been linked to risk of childhood ALL, including air pollution. Closely related to air pollution and human development is artificial light at night (ALAN), which is believed to disrupt circadian rhythm and impact health. We sought to evaluate outdoor ALAN and air pollution on risk of childhood ALL. The California Linkage Study of Early-Onset Cancers is a large population-based case–control in California that identifies and links cancer diagnoses from the California Cancer Registry to birth records. For each case, 50 controls with the same year of birth were obtained from birth records. A total of 2,782 ALL cases and 139,100 controls were identified during 2000–2015. ALAN was assessed with the New World Atlas of Artificial Night Sky Brightness and air pollution with an ensemble-based air pollution model of particulate matter smaller than 2.5 microns (PM2.5). After adjusting for known and suspected risk factors, the highest tertile of ALAN was associated with an increased risk of ALL in Hispanic children (odds ratio [OR] = 1.15, 95% confidence interval [CI] 1.01–1.32). There also appeared to be a borderline association between PM2.5 level and risk of ALL among non-Hispanic White children (OR per 10 µg/m3 = 1.24, 95% CI 0.98–1.56). We observed elevated risk of ALL in Hispanic children residing in areas of greater ALAN. Further work is needed to understand the role of ALAN and air pollution in the etiology of childhood ALL in different racial/ethnic groups.

Genetic variants in m5C modification core genes are associated with the risk of Chinese pediatric acute lymphoblastic leukemia: A five-center case-control study.

To explore the functions of the polymorphisms in 5-methylcytosine (m5C) modification-related coding genes on the susceptibility of pediatric acute lymphoblastic leukemia (ALL). Case-control study and multinomial logistic regression analysis were performed to construct models to evaluate the susceptibility of pediatric ALL. The relationship between five functional SNPs in m5C modification-coding genes and pediatric ALL risk was analyzed. Genotyping of 808 cases and 1,340 healthy samples from South China was identified using a TaqMan assay; odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the relationship between the five selected SNPs and pediatric ALL susceptibility. Among the five analyzed SNPs, NOL1 rs3764909 and NSUN4 rs10252 variants significantly increased the susceptibility of pediatric ALL, while NSUN3 rs7653521, NSUN5 rs1880948, and NSUN6 rs3740102 variants were not associated with the risk of ALL. Stratification analyses demonstrated that NOL1 rs3764909 C>A exhibited a significant association with increased pediatric ALL risk in subgroups of common B ALL, pre-B ALL, T-cell ALL, low and middle risk, other gene fusion types, non-gene fusion, hypodiploid, normal diploid, primitive lymphocytes in marrow < 5% on week 12, and minimal residual disease (MRD) <0.01% on week 12 after induced therapy; NSUN4 rs10252 G>A was related to increased risk of ALL children in subgroups of age ≥ 120 months, normal white blood cell (WBC) number, middle risk, non-gene fusion, MRD ≥ 0.01 on days 15-19, and primitive lymphocytes in marrow < 5% on day 33 after induced therapy. Compared with the reference haplotype CAGTA, children who harbored haplotypes CCGTG and ACATA were remarkably related to increased ALL susceptibility. rs3764909 and rs10252 varieties of alleles were not associated with MRD levels after the selected chemotherapeutics. In conclusion, NOL1 rs3764909 and NSUN4 rs10252 variants were enhanced by pediatric ALL risk and were suggested to be potential biomarkers for pediatric ALL.

Childcare attendance and risk of childhood acute lymphoblastic leukaemia: A register study based on the Danish childcare database.

Childhood acute lymphoblastic leukaemia (ALL) is suggested to result from a dysregulated immune response to infections in children with a preleukaemic state. Childcare in early life supposedly may protect against childhood ALL by facilitating sufficient exposure to infections to stimulate and ensure normal maturation of the immune system. We assessed the association between childcare attendance before age 2 years and risk of childhood ALL in a register-based cohort study, including all children aged 2 to 14 years born in Denmark during 1991 to 2014 with available childcare information recorded in the Danish Childcare Database (n=1 116 185). Cox regression was used to estimate hazard ratios (HRs) comparing children enrolled in childcare and children not enrolled before age 2 years. Further, we assessed the association according to age at enrolment, type of childcare facility and specific ALL subtypes. During 10 460 811 person-years of follow-up, 460 children developed ALL at ages 2 to 14 years. Of these, 57 (12.4%) never attended childcare before age 2 years compared with 10.6% in the total cohort. Compared with homecare, childcare attendance before age 2 years was associated with a statistically non-significantly, marginally decreased risk of childhood ALL with adjusted HR=0.87 (95% confidence interval [CI]: 0.65-1.16). Risk estimates did neither vary statistically significantly by age at enrolment nor by type of childcare facility and also not between childhood ALL subtypes, including frequently prenatally initiated ALL subtypes. Results from this large, nationwide register-based study provided no evidence that childcare attendance in the first years of life protects against childhood ALL.

Individual and combined effects of the GSTM1 and GSTT1 polymorphisms on acute lymphoblastic leukemia risk in Indian patients

Individual and combined effects of the GSTM1 and GSTT1 polymorphisms on acute lymphoblastic leukemia risk in Indian patients

Leukemogenesis in infants and young children with trisomy 21.

Children with Down syndrome (DS) have a greater than 100-fold increased risk of developing acute myeloid leukemia (ML) and an approximately 30-fold increased risk of acute lymphoblastic leukemia (ALL) before their fifth birthday. ML-DS originates in utero and typically presents with a self-limiting, neonatal leukemic syndrome known as transient abnormal myelopoiesis (TAM) that is caused by cooperation between trisomy 21-associated abnormalities of fetal hematopoiesis and somatic N-terminal mutations in the transcription factor GATA1. Around 10% of neonates with DS have clinical signs of TAM, although the frequency of hematologically silent GATA1 mutations in DS neonates is much higher (~25%). While most cases of TAM/silent TAM resolve without treatment within 3 to 4 months, in 10% to 20% of cases transformation to full-blown leukemia occurs within the first 4 years of life when cells harboring GATA1 mutations persist and acquire secondary mutations, most often in cohesin genes. By contrast, DS-ALL, which is almost always B-lineage, presents after the first few months of life and is characterized by a high frequency of rearrangement of the CRLF2 gene (60%), often co-occurring with activating mutations in JAK2 or RAS genes. While treatment of ML-DS achieves long-term survival in approximately 90% of children, the outcome of DS-ALL is inferior to ALL in children without DS. Ongoing studies in primary cells and model systems indicate that the role of trisomy 21 in DS leukemogenesis is complex and cell context dependent but show promise in improving management and the treatment of relapse, in which the outcome of both ML-DS and DS-ALL remains poor.

Periconceptional folate intake influences DNA methylation at birth based on dietary source in an analysis of pediatric acute lymphoblastic leukemia cases and controls

Periconceptional folate intake is associated with the establishment of DNA methylation in offspring; however, variations in this relation by food sources compared with folic acid supplements are not described. Also, maternal folate intake is associated with decreased risk of pediatric acute lymphoblastic leukemia (ALL), but the mechanism is not known. We evaluated the relation between periconceptional folate intake by source and DNA methylation at birth in a cohort of pediatric ALL cases and controls in an epigenome-wide association study. Genome-wide DNA methylation status obtained from archived neonatal blood spots from pediatric ALL cases (n=189) and controls (n=205) in the California Childhood Leukemia Study (CCLS) from 1995-2008 was compared with periconceptional folate from total, food, and supplemental sources using multivariable linear regression. Further stratification was performed by income, education, ethnicity, and total folate intake. We evaluated variable DNA methylation response to periconceptional folate by ALL case status through an interaction term. Two significant differentially methylated probes (DMPs) were associated with food and supplemental periconceptional folate intake in all subjects (n=394). The top differentially methylated region at the promoter region of DUSP22(dual specificity phosphatase 22) demonstrated DNA hypermethylation in ALL cases but not in controls in response to total and food folate intake. We further identified 8 interaction term DMPs with variable DNA methylation response to folate intake by ALL case status. Further stratification of the cohort by education and ethnicity revealed a substantially higher number of DMPs associated with supplemental folic acid intake in Hispanic subjects with lower income and educational level. We identified modest associations between periconceptional folate intake and DNA methylation differing by source, including variation by ALL case status. Hispanic subjects of lower income and education appear uniquely responsive to periconceptional folate supplementation.

Superior Graft-Versus-Leukemia Effect in Matched Unrelated Donor Versus HLA-Identical Sibling Pediatric Recipients Transplanted for Acute Lymphoblastic Leukemia within the Forum Study

Introduction: Allogeneic stem cell transplantation (HSCT) from either matched siblings (MSD) or matched unrelated donors (MUD) remains a standard option for children with high risk acute lymphoblastic leukemia (ALL), either in first complete remission (CR) or after relapse. The superiority of total body irradiation (TBI)/VP16 conditioning, compared to a chemotherapy based conditioning (fludarabine and thiotepa plus either busulfan or treosulfan) was demonstrated in theprospective, international, randomized non inferiority phase III study which enrolled 417 patients beyond the age of 4 years (y) transplanted for ALL in CR from either MSD or MD (Peters et al, JCO 2021; FORUM study). Besides the 201 patients randomized and actually receiving TBI from 2013 and 2018 in the randomizing countries, the FORUM trial included 411 additional children conditioned with TBI/VP16, enrolled either in countries where the randomization could not take place (for either legal or technical reasons) or in randomizing countries where TBI was chosen because the randomization was either skipped by physicians or families or had been discontinued. Methods: Here we report the 3-year consolidated results of these 612 patients ³4y and <21y treated in >100 pediatric centers in 26 countries following HSCT from either MSD (n=186, 30%) or MUD (defined as 9 or 10/10 4-digit molecular HLA-compatibility, n=426, 70%) after 12Gy TBI-VP16 for ALL in CR³1. Transplant details and statistical methods werepreviously reported in detail (Peters et al, JCO 2021). Of note, the main difference between the two groups was the GvHD prophylaxis consisting of cyclosporine A (CSA) +/- methotrexate (MTX) in MSD and serotherapy + CSA + MTX (Day 1, 3, 6, 11 post-HSCT) in MUD. Results: Patient's characteristics are reported in Table. Median age was 10y (4.0-20.8). The MSD and MUD groups were comparable, with the only exception of a larger use of peripheral blood and cord blood as stem cell source in the MUD population. In total, 299 pts were transplanted in CR1 (MSD, n=84; MUD, n=215) and 312 (MSD, n=102; MUD, n=210) in > CR1. In univariate analysis (figure), the Kaplan-Meier estimate of 3-year overall survival (OS) was significantly better in the MUD compared to the MSD group (83±2% vs 73±5%, respectively, P=0.041). Both the 3-year cumulative incidence (CI) of treatment-related mortality (TRM) and the 3-year probability of Event Free Survival (EFS) were comparable in the 2 groups analyzed (7±3% vs 7±1%, P=0.87 and 69±5% vs 83±2%, P=0.25, in MSD and MUD, respectively). The 3-year cumulative incidence of relapse (CIR) was higher in MSD (24±4% and 16±2%, respectively), although not statistically significant (p=0.08). The CI of acute GvHD was comparable in both groups, whereas the 3-year CI of cGvHD was higher in MSD than in MUD (19±3 vs 11±2%, P=0.07). The GvHD-relapse-secondary malignancy-free survival (GRFS) is significantly better in MUD than MSD (62±3 vs ±51±5%, P=0.04). In multivariate analysis, factors associated with superior OS include being transplanted from unrelated donor MUD, in CR1 and below the age of 14 years. Disease status at time of HSCT (i.e. CR1) was the only factor associated with better EFS and lower risk of post-transplant relapse. Conclusion: Our data indicate that the use of MUD is no longer a risk factor in HSCT for childhood ALL. The greater immune-genetic disparity in the matched unrelated donor/recipient pairs protects from the risk of disease recurrence, while the use of serotherapy prevents the occurrence of chronic GvHD, with both factors contributing to the observed improved GRFS in patients transplanted from an unrelated donor. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Racial and Ethnic Disparities in Childhood Acute Lymphoblastic Leukemia Risk Due to an IKZF1 Noncoding Regulatory Variant

Racial and Ethnic Disparities in Childhood Acute Lymphoblastic Leukemia Risk Due to an IKZF1 Noncoding Regulatory Variant

First experience of total body irradiation in conditioning regimes for allogenic hematopoietic stem cells transplantation in children with acute lymphoblastic leukemia in Saint Petersburg

Background. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment method of refractory and recurrent forms of acute leukemia in children, while the question of choosing a conditioning regimen in order to achieve the best treatment results remains debatable. Conditioning based on total body irradiation (TbI) was confirmed to be most effective in some trials, but there are still issues of overcoming early and late toxicity, as well as difficulties in planning and routing patients.Aim. To share the experience of interdisciplinary patient management during the conditioning period with TbI inclusion in Saint petersburg, to evaluate the feasibility, toxicity and effectiveness of the method.Materials and methods. patients undergoing allo-HSCT for high risk acute lymphoblastic leukemia conditioned either with TbI (n = 12) or chemotherapy (n = 10) were included. Medical data were retrospectively analyzed with an assessment of the following transplant outcomes: HSCT-associated toxicity, the frequency and severity of infectious complications, graft versus host disease, as well as overall and event-free survival rates. we have evaluated radiotherapy plans in order to assess the compliance of radiation exposure with acceptable values for critical organs.Results. All patients with acute lymphoblastic leukemia in both groups received appropriate myeloablative conditioning. According to the study results, despite the lack of significance, we obtained differences in HSCT-associated mortality (8.3 and 30 %; p = 0.151), 2-years overall and event-free survival (66 ± 13.6 and 36 ± 16.1 %; p = 0.122) in group with TbI and HdCT respectively. It should be noted that there was a trend towards a decrease of toxic reactions frequency in case of TbI-containing regimens; however we didn’t reveal any significant differences in the number of infectious complications during post-transplant period. The median follow-up was 24.2 months and there were no signs of delayed toxicity.Conclusion. TbI-based conditioning was well tolerated with a low incidence of early and delayed toxicity, better overall and event-free survival. based on feasibility of TbI in Saint petersburg hospitals it is possible to recommend the method in routine practice, taking into account clinical indications.

Relationship between IKZF1 polymorphisms and the risk of acute lymphoblastic leukemia: a meta-analysis*

Abstract Objective The aim of the study was to systematically evaluate the correlation between IKZF1 polymorphisms and the risk of acute lymphoblastic leukemia. Methods Computer databases including PubMed, EMBASE, and Web of Science were searched for case-control studies on the association between IKZF1 polymorphisms and the risk of acute lymphoblastic leukemia. The retrieval period was from the establishment of the database to November 2020. Two researchers independently screened the literature, extracted the data, evaluated the risk of bias in the included studies, and used Stata 14.0 software for meta-analysis. Results A total of 48 case-control studies were included, with 10 520 and 44 049 cases in the case and control groups, respectively. The meta-analysis results showed that rs4132061 and rs11978267 of IKZF1 were significantly correlated with the risk of acute lymphoblastic leukemia (ALL). Conclusion Current evidence indicates that rs4132061 and rs11978267 of IKZF1 are significantly associated with the risk of B-cell ALL.

THE ACUTE LYMPHOBLASTIC LEUKEMIA OF DOWN SYNDROME

Down syndrome (DS) is a genetic disorder caused by the presence of a third copy of chromosome 21.It is usually associated with physical growth delays, mild to moderate intellectual disability, and characteristic facial features .Children with DS are at an elevated risk of leukemia, especially myeloid leukemia. On the other hand, children with DS are at a 20-fold increased risk for acute lymphoblastic leukemia (ALL).In our case, we presented a patient with DS who was diagnosed with ALL. 19-year-old male was admitted to the emergency department due to abdominal pain.On his physical examination,splenomegaly was detected.In laboratory examinations; kidney and liver function tests were normal,lactate dehydrogenase:372 U/L,uric acid: 5.4 mg/dl,white blood cell:25000 × 106/L,lymphocyte: 15780 × 106/L, neutrophil:1140 × 106/L,hemoglobin:10 gr/dl, thrombocyte:12000 × 106/L,coagulation tests were normal and in peripheral blood smear evaluation,90% blast cells were detected. Peripheral blood flow cytometry evaluation was compatible with B-ALL(TdT,CD19,CD10,CD34,cCD79a,CD58,CD9,CD38,CD123,CD20,CD81,CD22 positivity in atypical cells).Bone marrow biopsy was hypercellular.There was diffuse blastic cell infiltration,which stained extensively with TDT,CD79a.Chromosomal analysis is 47XY,+21 and t(12,21) (p13.2;q22.12) (ETV6/RUNX1) (FISH) and 14q32.33 (IGH) FISH were positive,t(9;22) P190 -p210,t(4;11), t(1;19),11q23 were negative.The risk classification was standard risk. AUGMENTED BFM induction chemotherapy protocol was started.Pancreatitis was developed after peg-asparaginase and chemotherapy-related hepatotoxicity(grade 1) was developed.Central nervous system prophylaxis(intrathecal methotrexate) was applied.The control bone marrow biopsy performed after induction was normocellular,the blast rate was <5%.BFM standard risk first consolidation chemotherapy protocol was started.He died of septic shock on the eighteenth day of the first consolidation treatment. Cases of DS-ALL cases are at greater risk for serious side effects from chemotherapeutics,mortality and recurrence than non DS-ALL.Because children with DS have a higher incidence of treatment-related toxicity,survival rates are lower than non-DS children.During ALL induction chemotherapy life-threatening side effects are tumor lysis syndrome,thrombosis,bleeding and infection.In the UKALL 2003 study,DS associated with a significantly increased risk of death from sepsis during chemotherapy.

ACUTE KIDNEY INJURY IN PATIENTS WITH ACUTE LEUKEMIA AFTER HEMATOPOIETIC STEM CELL TRANSPLANTATION: A SERIES OF CLINICAL CASES

Relevance: Acute renal kidney injury is a severe complication in patients with acute leukemia who underwent hematopoietic stem cell&#x0D; transplantation (HSCT). According to statistics, acute renal dysfunction often occurs in the first 100 days after HSCT.&#x0D; This study aimed to evaluate kidney function in patients with acute leukemia after hematopoietic stem cell transplantation.&#x0D; Methods: The article presents clinical cases of patients with acute lymphoblastic leukemia who developed acute renal failure after&#x0D; HSCT. The dynamics of the functional state of kidneys in patients with acute lymphoblastic leukemia after HSCT are described.&#x0D; Results: The acute kidney disorder in the studied patients was mainly caused by HSCT complications. We have identified renal kidney&#x0D; damage in the form of acute tumor lysis and thrombotic microangiopathy.&#x0D; Conclusion: Patients with acute lymphoblastic leukemia risk developing acute kidney disorder during HSCT, which requires careful&#x0D; monitoring of kidney function, especially in the early post-transplant period

ACUTE RENAL DISORDER IN PATIENTS WITH ACUTE LEUKEMIA&#x0D; AFTER HEMATOPOIETIC STEM CELL TRANSPLANTATION:&#x0D; A SERIES OF CLINICAL CASES

Relevance: Acute renal kidney disorder is a serious complication in patients with acute leukemia who underwent hematopoietic stem cell&#x0D; transplantation (HSCT). According to statistics, acute renal dysfunction often occurs in the first 100 days after HSCT.&#x0D; This study aimed to evaluate kidney function in patients with acute leukemia after hematopoietic stem cell transplantation.&#x0D; Methods: The article presents clinical cases of patients with acute lymphoblastic leukemia who developed acute renal failure after HSCT. The&#x0D; dynamics of the functional state of kidneys in patients with acute lymphoblastic leukemia after HSCT are described.&#x0D; Results: The acute kidney disorder in the studied patients was mainly caused by HSCT complications. We have identified renal kidney damage&#x0D; in the form of acute tumor lysis and thrombotic microangiopathy.&#x0D; Conclusion: Patients with acute lymphoblastic leukemia risk developing acute kidney disorder during HSCT, which requires careful monitoring of kidney function, especially in the early post-transplant period.

Transcriptomic Analysis of Conserved Telomere Maintenance Component 1 (CTC1) and Its Association with Leukemia.

Telomere length (TEL) regulation is important for genome stability and is governed by the coordinated role of shelterin proteins, telomerase (TERT), and CST (CTC1/OBFC1/TEN1) complex. Previous studies have shown the association of telomerase expression with the risk of acute lymphoblastic leukemia (ALL). However, no data are available for CST association with the ALL. The current pilot study was designed to evaluate the CST expression levels in ALL. In total, 350 subjects were recruited, including 250 ALL cases and 100 controls. The subjects were stratified by age and categorized into pediatrics (1–18 years) and adults (19–54 years). TEL and expression patterns of CTC1, OBFC1, and TERT genes were determined by qPCR. The univariable logistic regression analysis was performed to determine the association of gene expression with ALL, and the results were adjusted for age and sex in multivariable analyses. Pediatric and adult cases did not reflect any change in telomere lengths relative to controls. However, expression of CTC1, OBFC1, and TERT genes were induced among ALL cases. Multivariable logistic regression analyses showed association of CTC1 with ALL in pediatric [β estimate (standard error (SE)= −0.013 (0.007), p = 0.049, and adults [0.053 (0.023), p = 0.025]. The association of CTC1 remained significant when taken together with OBFC1 and TERT in a multivariable model. Furthermore, CTC1 showed significant association with B-cell ALL [−0.057(0.017), p = 0.002) and T-cell ALL [−0.050 (0.018), p = 0.008] in pediatric group while no such association was noted in adults. Together, our findings demonstrated that telomere modulating genes, particularly CTC1, are strongly associated with ALL. Therefore, CTC1 can potentially be used as a risk biomarker for the identification of ALL in both pediatrics and adults.

Clusters of small-scale sources of air carcinogens emissions increase the risks of acute lymphoblastic leukemia (ALL) in children and teenagers at a small area level in urban areas

Clusters of small-scale sources of air carcinogens emissions increase the risks of acute lymphoblastic leukemia (ALL) in children and teenagers at a small area level in urban areas

Glyphosate in house dust and risk of childhood acute lymphoblastic leukemia in California

Glyphosate in house dust and risk of childhood acute lymphoblastic leukemia in California

Association of Toll-like receptors polymorphisms with the risk of acute lymphoblastic leukemia in the Brazilian Amazon

Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in children in childhood. Single-nucleotide polymorphism (SNPs) in key molecules of the immune system, such as Toll-like receptors (TLRs) and CD14 molecules, are associated with the development of several diseases. However, their role in ALL is unknown. A case–control study was performed with 152 ALL patients and 187 healthy individuals to investigate the role of SNPs in TLRs and the CD14 gene in ALL. In this study, TLR6 C > T rs5743810 [OR: 3.20, 95% CI: 1.11–9.17, p = 0.003) and TLR9 C > T rs187084 (OR: 2.29, 95% CI: 1.23–4.26, p = 0.000) seems to be a risk for development of ALL. In addition, the TLR1 T > G rs5743618 and TLR6 C > T rs5743810 polymorphisms with protection against death (OR: 0.17, 95% IC: 0.04–0.79, p = 0.008; OR: 0.48, 95% IC: 0.24–0.94, p = 0.031, respectively). Our results show that SNPs in TLRs genes may be involved in the pathogenesis of ALL and may influence clinical prognosis; however, further studies are necessary to elucidate the role of TLR1, TLR4, TLR5, TLR6, TLR9 and CD14 polymorphisms in this disease.

ARID5B influences B-cell development and function in mouse.

There is growing evidence for an inherited basis of susceptibility to childhood acute lymphoblastic leukemia. Genomewide association studies by us and others have identified non-coding acute lymphoblastic leukemia risk variants at the ARID5B gene locus, but the molecular mechanisms linking ARID5B to normal and malignant hematopoiesis remain largely unknown. Using a Vav1-driven transgenic mouse model, we characterized the role of Arid5b in hematopoiesis in vivo. Arid5b overexpression resulted in a dramatic reduction in the proportion of circulating B cells, immature, and mature Bcell fractions in the peripheral blood and the bone marrow, and also a decrease of follicular B cells in the spleen. There were significant defects in B-cell activation upon Arid5b overexpression in vitro with hyperactivation of B-cell receptor signaling at baseline. In addition, increased mitochondrial oxygen consumption rate of naïve or stimulated B cells of Arid5b-overexpressing mice was observed, compared to the rate of wild-type counterparts. Taken together, our results indicate that ARID5B may play an important role in B-cell development and function.

Unconventional Oil and Gas Development Exposure and Risk of Childhood Acute Lymphoblastic Leukemia: A Case-Control Study in Pennsylvania, 2009-2017.

Background:Unconventional oil and gas development (UOGD) releases chemicals that have been linked to cancer and childhood leukemia. Studies of UOGD exposure and childhood leukemia are extremely limited.Objective:The objective of this study was to evaluate potential associations between residential proximity to UOGD and risk of acute lymphoblastic leukemia (ALL), the most common form of childhood leukemia, in a large regional sample using UOGD-specific metrics, including a novel metric to represent the water pathway.Methods:We conducted a registry-based case–control study of 405 children ages 2–7 y diagnosed with ALL in Pennsylvania between 2009–2017, and 2,080 controls matched on birth year. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between residential proximity to UOGD (including a new water pathway-specific proximity metric) and ALL in two exposure windows: a primary window (3 months preconception to 1 y prior to diagnosis/reference date) and a perinatal window (preconception to birth).Results:Children with at least one UOG well within of their birth residence during the primary window had 1.98 times the odds of developing ALL in comparison with those with no UOG wells [95% confidence interval (CI): 1.06, 3.69]. Children with at least one vs. no UOG wells within during the perinatal window had 2.80 times the odds of developing ALL (95% CI: 1.11, 7.05). These relationships were slightly attenuated after adjusting for maternal race and socio-economic status [odds ratio (OR) (95% CI: 0.93, 3.27) and (95% CI: 0.93, 5.95)], respectively). The ORs produced by models using the water pathway-specific metric were similar in magnitude to the aggregate metric.Discussion:Our study including a novel UOGD metric found UOGD to be a risk factor for childhood ALL. This work adds to mounting evidence of UOGD’s impacts on children’s health, providing additional support for limiting UOGD near residences. https://doi.org/10.1289/EHP11092

Investigating DNA methylation as a mediator of genetic risk in childhood acute lymphoblastic leukemia.

Genome-wide association studies have identified a growing number of single nucleotide polymorphisms (SNPs) associated with childhood acute lymphoblastic leukemia (ALL), yet the functional roles of most SNPs are unclear. Multiple lines of evidence suggest that epigenetic mechanisms may mediate the impact of heritable genetic variation on phenotypes. Here, we investigated whether DNA methylation mediates the effect of genetic risk loci for childhood ALL. We performed an epigenome-wide association study (EWAS) including 808 childhood ALL cases and 919 controls from California-based studies using neonatal blood DNA. For differentially methylated CpG positions (DMPs), we next conducted association analysis with 23 known ALL risk SNPs followed by causal mediation analyses addressing the significant SNP-DMP pairs. DNA methylation at CpG cg01139861, in the promoter region of IKZF1, mediated the effects of the intronic IKZF1 risk SNP rs78396808, with the average causal mediation effect (ACME) explaining ~30% of the total effect (ACME P = 0.0031). In analyses stratified by self-reported race/ethnicity, the mediation effect was only significant in Latinos, explaining ~41% of the total effect of rs78396808 on ALL risk (ACME P = 0.0037). Conditional analyses confirmed the presence of at least three independent genetic risk loci for childhood ALL at IKZF1, with rs78396808 unique to non-European populations. We also demonstrated that the most significant DMP in the EWAS, CpG cg13344587 at gene ARID5B (P = 8.61×10-10), was entirely confounded by the ARID5B ALL risk SNP rs7090445. Our findings provide new insights into the functional pathways of ALL risk SNPs and the DNA methylation differences associated with risk of childhood ALL.