Increased Risk Of Leukemia Research Articles

Environmental/Occupational Exposure to Radon and Non-Pulmonary Neoplasm Risk: A Review of Epidemiologic Evidence.

Although Radon (Rn) is a known agent for lung cancer, the link between Rn exposure and other non-pulmonary neoplasms remains unclear. The aim of this review is to investigate the role of Rn in the development of tumors other than lung cancer in both occupational and environmental exposure. Particularly, our attention has been focused on leukemia and tumors related to brain and central nervous system (CNS), skin, stomach, kidney, and breast. The epidemiologic literature has been systematically reviewed focusing on workers, general population, and pediatric population. A weak increase in leukemia risk due to Rn exposure was found, but bias and confounding factors cannot be ruled out. The results of studies conducted on stomach cancer are mixed, although with some prevalence for a positive association with Rn exposure. In the case of brain and CNS cancer and skin cancer, results are inconclusive, while no association was found for breast and kidney cancers. Overall, the available evidence does not support a conclusion that a causal association has been established between Rn exposure and the risk of other non-pulmonary neoplasms mainly due to the limited number and heterogeneity of existing studies. To confirm this result, a statistical analysis should be necessary, even if it is now not applicable for the few studies available.

Increased Leukemia Risk in Children With Down Syndrome

Research Article| October 01 2021 Increased Leukemia Risk in Children With Down Syndrome AAP Grand Rounds (2021) 46 (4): 45. https://doi.org/10.1542/gr.46-4-45 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation Increased Leukemia Risk in Children With Down Syndrome. AAP Grand Rounds October 2021; 46 (4): 45. https://doi.org/10.1542/gr.46-4-45 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search nav search search input Search input auto suggest search filter All PublicationsAll JournalsAAP Grand RoundsPediatricsHospital PediatricsPediatrics In ReviewNeoReviewsAAP NewsAll AAP Sites Search Advanced Search Topics: down syndrome, leukemia Source: Marlow EC, Ducore J, Kwan ML, et al Leukemia risk in a cohort of 3.9 million children with and without Down syndrome. J Pediatr. 2021;234:172-180.e3; doi:10.1016/j.jpeds.2021.03.001Google Scholar Investigators from multiple institutions conducted a retrospective cohort study to assess leukemia risks in children with Down syndrome. For the study, they included data on all live births at 7 US healthcare systems and in Ontario, Canada, between 1996 and 2016. Children with Down syndrome were identified by ICD-9 and ICD-10 codes. Cancer diagnoses were obtained from tumor registries in the US and the Pediatric Oncology Group of Ontario Networked Information System. Additional information collected included sex, age, and maternal age at birth; race and ethnicity data were available on US children. Study participants were followed until age 15, any cancer diagnosis, death, or disenrollment from the healthcare system. The primary study outcome was incident diagnosis of primary leukemia and incident diagnosis of specific leukemias including acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and megakaryoblastic leukemia (AML-M7) based on the 2008 WHO classification. The incidence of leukemia (overall and by subtype) in children with Down syndrome and those without was compared using Cox proportional hazard models, with analyses stratified by age (<5 and ≥5 years old). Data were analyzed on 3,905,399 children, including 4,401 with Down syndrome (incidence 1.12/1,000 children). Study participants with Down syndrome were more likely to be male (54.7% vs 51.3% in those without Down syndrome), born to mothers ≥40 years old (18.6% vs 3.7%), and in the US cohort more likely to be white (73.1% vs 65.0%) and of Hispanic ethnicity (24.8% vs 19.3%). Among children with Down syndrome, the incidence of AML peaked in the first year of life (incidence 619.4 per 100,000), with ALL becoming more common in those 2 to 4 years old (incidence ranging from 333.3 to 326.8/100,000). For other children, the incidence of AML was low at all ages (≤1.1/100,000); the incidence of ALL peaked at age 3 years (11.2/100,000). Down syndrome was associated with an increased risk for any leukemia (hazard ratio [HR], 75.6; 95% CI, 62.3, 91.6 for those <5 years old; HR, 18.3; 95% CI, 7.8, 43.1 for those ≥5 years old). Among those <5 years old, Down syndrome was associated with an increased risk of AML-M7 (HR, 1,500; 95% CI, 555, 4,070) and other AML (HR, 197; 95% CI, 70, 553). Children with Down syndrome also were at increased risk for ALL (HR, 28.4; 95% CI, 20.4, 39.6 for those <5 years old; HR, 21.4; 95% CI, 12.1, 37.9 for those ≥5 years old). The authors conclude that Down syndrome is a strong risk factor for childhood leukemia. Dr Hogan has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device. Down syndrome (DS), arising in an estimated 1 in 800 to 1,000 live births in the US annually,1 is... You do not currently have access to this content.

Impact of Bioflavonoid Exposure on DNA Damage Response and of Non-Homologous End Joining (NHEJ) Pathway Repair Proteins in Stem Cells

DNA double-strand breaks (DSBs) activate DNA damage response signaling pathways and multiple repair pathways depending on cell cycle stage and differentiation state. An array of recurrent, non-random chromosomal translocations are associated with hematologic malignancies, and we are interested in determining the role of specific DNA repair proteins or pathway choice in the etiology of these rearrangements. Classic non-homologous end joining (NHEJ) utilizes LIG4, XRCC4, and XLF during the final steps; LIG4 and XRCC4 deficiency is implicated in both leukemais and lymphomas but the role of XLF deficiency in leukemia etiology is not clear. Activation of alternative NHEJ (Alt-NHEJ) is largely dependent on CtIP that promotes the resection of DNA ends to uncover micro-homologies promoting the formation of large deletions and chromosomal translocations. Studies suggest that loss of efficient activity in one NHEJ repair pathway may promote use of the other more error-prone pathway. The topoisomerase II poison etoposide is a cytotoxic chemotherapeutic agent associated with therapy-related leukemias characterized by translocations involving the MLL gene at 11q23. Leukemias with MLL gene fusions have been detected in newborns indicating that these translocations can occur in utero, and additional evidence from our lab and others suggests maternal exposure to environmental topoisomerase II inhibitors such as bioflavonoids have the potential to promote these events. We are interested in understanding the crosstalk involved in bioflavonoid exposure, DNA damage response signaling, and repair pathway choice as a model system to understand the underlying mechanisms of oncogenic transformation in infant leukemias.Using established in vitro differentiation protocols, we expose embryonic stem (ES) cells and hematopoietic stem cells (HSC) derived from them to a panel of bioflavonoids alone or in combination for one hour at increasing doses ranging from 0μM-200μM based on determined LD50 values. As a control, cells are exposed to etoposide at the same doses. Following exposure, cells recovered for a period of 0-24hrs, followed by protein extraction and Western blotting. Quantitation of increases in total gH2AX confirm DNA damage, presence of Ku70 and XLF to support classical NHEJ, and CtIP to support Alt-NHEJ. Cells exposed to bioflavonoids genistein and quercetin as well as etoposide show elevated γH2AX levels by 4 hrs post-treatment compared to untreated cells. Parallel studies show dose-dependent increase in the presence of γH2AX foci in these cells. These results confirm that although bioflavonoids have pleiotropic effects, they directly promote DSBs in a short period of time post-exposure. Protein levels of Ku70 and XLF in cells exposed to genistein, quercetin, and etoposide at doses of 25, 50, 75 and 100μM are not significantly different from untreated cells. However, CtIP levels are elevated in cells exposed to quercetin compared to all other groups suggesting a specific potential for this bioflavonoid to promote Alt-NHEJ repair and genome instability.To correlate the activity of these DNA repair protein activities with downstream repair products, we use a model cell system in which parental ES cells were engineered to contain two constructs: GFP exons inserted into MLL and AF9 bcr transgene fragments. Aberrant repair resulting in chromosomal translocations are scored by GFP+ fluorescence. In both ES and derived HSC populations from them translocations can be scored following exposure to bioflavonoids and etoposide. Ongoing experiments include downregulation of XLF or CtIP by siRNA in cells prior to exposure to these compounds. Results will be presented on impact of downregulation of these two NHEJ proteins on 1) amount and persistence of γH2AX; 2) protein levels of other DNA repair pathway proteins, and 3) frequency of generating chromosomal translocations.Understanding the integrated activity and role of these proteins in preventing or promoting translocations, particularly in the context of exposure to a wide range of environmental and dietary compounds, will be critical to understanding the potential for specific isoforms or mutants to increase leukemia risk. DisclosuresNo relevant conflicts of interest to declare.

Sowing the Seeds of Clonal Hematopoiesis.

As humans age, hematopoietic stem cells (HSCs) occasionally acquire mutations in genes including DNMT3A that enable them to outcompete other HSCs and increase leukemia risk. In this issue of Cell Stem Cell, Tovy etal. (2020) report a previously uncharacterized mechanism by which DNMT3A loss confers increased fitness to HSCs by analyzing a rare experiment of nature.

Asbestos exposure and haematological malignancies: a Danish cohort study

Environmental asbestos exposure and occupational asbestos exposure increase the risk of several types of cancer, but the role of such exposures for haematological malignancies remains controversial. We aimed to examine the risk of haematological malignancies: first, in subjects exposed early in life, independently of any occupational exposure occurring later; second, in subjects exposed occupationally. We established an environmentally exposed cohort from four schools located near the only former asbestos cement production plant in Denmark. We identified nearly all pupils in the seventh grade and created an age and sex-matched 1:9 reference cohort from the Danish Central Population Register. Participants were born 1940–1970 and followed up in national registers until the end of 2015. Occupational asbestos exposure was assessed for all participants using two different job exposure matrices. The school cohort included 12,111 participants (49.7% girls) and the reference cohort 108,987 participants. Eight subgroups of haematological malignancy were identified in the Danish Cancer Registry. These cases were analysed for combined overall haematological malignancy, a combined subgroup of lymphomas and a combined subgroup of leukaemias. The data were analysed using Cox regression (hazard ratios (HR)) including other cancers and death as competing risks. Haematological malignancy was identified in 1125 participants. The median follow-up was 49.3 years (0.1–63.4). Early environmental asbestos exposure was not associated with an increased risk of haematological malignancy. Long-term occupational asbestos exposure was associated with overall haematological malignancy (HR 1.69, 95% CI 1.04–2.73); in particular for the leukaemia subgroup (HR 2.14, 95% CI 1.19–3.84). This large follow-up study suggests that long-term occupational asbestos exposure is associated with increased leukaemia risk. However, further studies are needed to confirm these observations.

Risk of Leukemia Associated with Protracted Low-Dose Radiation Exposure: Updated Results from the National Registry for Radiation Workers Study.

While the link between risk of leukemia and acute radiation exposure is well established for large doses received acutely, uncertainty remains around the translation of these risk estimates to occupational exposure scenarios where the doses are low and accumulated over time, possibly over many years. We present leukemia incidence and mortality radiation risk estimates derived from the National Registry for Radiation Workers, which is a large cohort of occupationally exposed workers from the United Kingdom (UK). The cohort comprised 173,081 workers from the UK who were monitored for occupational exposure to radiation. The cohort was followed for a total of 5.3 million person-years and the incidence and mortality due to leukemia was identified through to the end of follow-up in 2011. Poisson regression was used to investigate the relationship between cumulative radiation dose and leukemia mortality and incidence rates using excess relative risk (ERR) and excess additive risk (EAR) models. The results of this work showed a collective dose of 4,414 person-Sv accumulated by the cohort with an average cumulative dose of 25.5 mSv. Among male workers both the ERR and EAR models showed evidence of increased leukemia risk (excluding chronic lymphatic leukemia) associated with increasing cumulative dose. The ERR was 1.38 per Sv (90% CI: 0.04; 3.24) and EAR was 1.33 per 10,000 person-year-Sv (90% CI: 0.04; 2.89) when a linear model was used. These excess risks were driven by increased risks for chronic myeloid leukemia [ERR/Sv = 6.77 (90% CI: 2.14; 15.44)]. In conclusion, this study provides further evidence that leukemia risks may be increased by low-dose and protracted external radiation exposure. The risks are generally consistent with those observed in the atomic bomb survivor studies, as well as with risk coefficients on which international radiation safety standards, including the dose limits and constraints used to control exposures, are based.

Trisomy of a Down Syndrome Critical Region Globally Amplifies Transcription via HMGN1 Overexpression

SUMMARYDown syndrome (DS, trisomy 21) is associated with developmental abnormalities and increased leukemia risk. To reconcile chromatin alterations with transcriptome changes, we performed paired exogenous spike-in normalized RNA and chromatin immunoprecipitation sequencing in DS models. Absolute normalization unmasks global amplification of gene expression associated with trisomy 21. Overexpression of the nucleosome binding protein HMGN1 (encoded on chr21q22) recapitulates transcriptional changes seen with triplication of a Down syndrome critical region on distal chromosome 21, and HMGN1 is necessary for B cell phenotypes in DS models. Absolute exogenous-normalized chromatin immunoprecipitation sequencing (ChIP-Rx) also reveals a global increase in histone H3K27 acetylation caused by HMGN1. Transcriptional amplification downstream of HMGN1 is enriched for stage-specific programs of B cells and B cell acute lymphoblastic leukemia, dependent on the developmental cellular context. These data offer a mechanistic explanation for DS transcriptional patterns and suggest that further study of HMGN1 and RNA amplification in diverse DS phenotypes is warranted.

Childhood cancer research in oxford III: The work of CCRG on ionising radiation

BackgroundHigh doses of ionising radiation are a known cause of childhood cancer and great public and professional interest attaches to possible links between childhood cancer and lower doses, particularly of man-made radiation. This paper describes work done by the Childhood Cancer Research Group (CCRG) on this topicMethodsMost UK investigations have made use of the National Registry of Childhood Tumours and associated controls. Epidemiological investigations have included national incidence and mortality analyses, geographical investigations, record linkage and case-control studies. Dosimetric studies use biokinetic and dosimetric modelling.ResultsThis paper reviews the work of the CCRG on the association between exposure to ionising radiation and childhood cancer, 1975–2014.ConclusionThe work of CCRG has been influential in developing understanding of the causes of 'clusters' of childhood cancer and the risks arising from exposure to ionising radiation both natural and man-made. Some clusters around nuclear installations have certainly been observed, but ionising radiation does not seem to be a plausible cause. The group’s work has also been instrumental in discounting the hypothesis that paternal preconception irradiation was a cause of childhood cancers and has demonstrated an increased leukaemia risk for children exposed to higher levels of natural gamma-ray radiation.

Associations Between XPD Lys751Gln Polymorphism and Leukemia: A Meta-Analysis.

Objectives: The aim of the present study was to define the potential relationship between xeroderma pigmentosum group D (XPD) Lys751Gln polymorphisms and the risk of leukemia.Methods: A comprehensive search of Pubmed, Web of Science, EBSCO, the Cochrane Library and China National Knowledge Infrastructure was conducted to identify original articles published before March 2017 concerning the association between XPD Lys751Gln polymorphisms and leukemia risk. A literature quality assessment was performed using the Newcastle-Ottawa Scale. Heterogeneity across studies was assessed using I2 statistics. Random- or fixed-effects models were used to calculate pooled odds ratios (ORs) in the presence or absence of heterogeneity, respectively. Sensitivity analysis was used to assess the influence of individual studies on the pooled estimate. Publication bias was investigated using funnel plots and Egger’s regression test. All data analyses were performed using Stata 14.0 and Revman 5.3.Results: Fourteen studies with a total of 7525 participants (2,757 patients; 4,768 controls) were included in this meta-analysis. We found that XPD Lys751Gln polymorphisms significantly increased the risk of developing leukemia in both dominant OR = 1.21, 95%CI [1.10–1.35], P ≤ 0.001) and heterozygote (OR = 1.22, 95%CI [1.09–1.36], P ≤ 0.001) model. An allele model showed a borderline significant increase in leukemia risk (OR = 1.13, 95%CI [1.00–1.27], P = 0.05). A subgroup analysis revealed a consistent association between XPD Lys751Gln polymorphisms and leukemia risk for some genetic models in Caucasian populations, adult or chronic groups, and in almost all models of childhood or acute groups.Conclusion: Our results indicate that XPD Lys751Gln polymorphism increases the risk of leukemia, especially in childhood and acute cases.

Effects Of Obesity And Exercise On Bone Marrow And Leukemia Cells Following Radiation

Radiation-induced leukemia is a serious late effect of radiation therapy partially due to long-term alterations in the bone marrow (BM) environment. Obesity and sedentary lifestyles, two host factors that remodel the bone marrow, are common amongst cancer survivors and linked to increase leukemia risk. Whether alterations to the bone marrow environment induced by obesity and physical activity alter leukemia risk following ionizing radiation (IR) exposure remains unknown. PURPOSE: Determine how exercise training and obesity modulate the BM environment and leukemia blast viability following sub-lethal IR exposure. METHODS: 4 week old CBA mice were fed a control (CON; n=20) or 45% high fat diet (HF; n=20). At 9 weeks old, CON and HF mice were divided into sedentary (SED, n=10) or exercise groups (EX, n=10). At 13 weeks, mice were administered a uniform radiation dose of 3 Gy and continued their specific diet and exercise regimen for 4 weeks. BM stromal cells were quantified by flow cytometry and marrow adipose tissue (MAT) was determined by μCT. Conditioned media (CM) from isolated BM stromal cells was analyzed by cytokine array and applied to the KG-1 leukemia cell line to assess cell viability by MTT assay. RESULTS: The number of mesenchymal stromal cells in CON+EX increased compared to CON+SED (p<0.05). EX increased the quantity of osteoblasts and endothelial progenitor cells compared to SED mice (both p<0.05). EX reduced MAT compared to SED, even in the presence of HF diet following sub-lethal IR (p<0.05). Inflammatory cytokines were also increased in the CM of HF-SED compared to CON-SED, and this effect was reduced with EX. CM from HF mice increased KG-1 viability, but not CM from EX (p<0.05). CONCLUSION: Overall, exercise increased BM stromal cell content and reduced BM inflammation while obesity increased BM adiposity and leukemia cell viability. These data suggest that exercise may be a therapeutic intervention to reduce secondary leukemias following radiation therapy, particularly in obese cancer survivors.

Estimation of the Leukemia Risk in Human Populations Exposed to Benzene from Tobacco Smoke Using Epidemiological Data.

Several epidemiological studies have demonstrated an association between occupational benzene exposure and increased leukemia risk, in particular acute myeloid leukemia (AML). However, there is still uncertainty as to the risk to the general population from exposure to lower environmental levels of benzene. To estimate the excess risk of leukemia from low-dose benzene exposure, various methods for incorporating epidemiological data in quantitative risk assessment were utilized. Tobacco smoke was identified as one of the main potential sources of benzene exposure and was the focus of this exposure assessment, allowing further investigation of the role of benzene in smoking-induced leukemia. Potency estimates for benzene were generated from individual occupational studies and meta-analysis data, and an exposure assessment for two smoking subgroups (light and heavy smokers) carried out. Subsequently, various techniques, including life-table analysis, were then used to evaluate both the excess lifetime risk and the contribution of benzene to smoking-induced leukemia and AML. The excess lifetime risk for smokers was estimated at between two and six additional leukemia deaths in 10,000 and one to three additional AML deaths in 10,000. The contribution of benzene to smoking-induced leukemia was estimated at between 9% and 24% (Upper CL 14-31%). For AML this contribution was estimated as 11-30% (Upper CL 22-60%). From the assessments carried out here, it appears there is an increased risk of leukemia from low-level exposure to benzene and that benzene may contribute up to a third of smoking-induced leukemia. Comparable results from using methods with varying degrees of complexity were generated.

Down syndrome, RASopathies, and other rare syndromes

In this article we discuss the occurrence of myeloid neoplasms in patients with a range of syndromes that are due to germline defects of the RAS signaling pathway and in patients with trisomy 21. Both RAS mutations and trisomy 21 are common somatic events contributing to leukemogenis. Thus, the increased leukemia risk observed in children affected by these conditions is biologically highly plausible. Children with myeloid neoplasms in the context of these syndromes require different treatments than children with sporadic myeloid neoplasms and provide an opportunity to study the role of trisomy 21 and RAS signaling during leukemogenesis and development.

PCTP (Phosphatidylcholine Transfer Protein) is Regulated By RUNX1 in Platelets/Megakaryocytes and is Associated with Adverse Cardiovascular Events

Transcription factor (TF) mutations are increasingly recognized to play a major role in inherited platelet abnormalities. RUNX1, a major hematopoietic TF, acts in a combinatorial manner with other TFs to regulate numerous megakaryocyte (MK)/platelet genes. Human RUNX1 haplodeficiency is associated with thrombocytopenia, platelet function defects, and increased leukemia risk. We have described a patient with multiple abnormalities in platelet aggregation and secretion responses with a heterozygous RUNX1 nonsense mutation (Sun et al Blood 2004; 103; 948-54). Transcript expression profiling of patient platelets (Sun et al J Thromb Haemost 2007; 5:146-54)showed several genes were significantly downregulated, including myosin light chain (MYL9), platelet factor 4 (PF4), protein kinase C-θ (PRCKQ), and 12-lipoxygenase (ALOX12); these have been shown by us to be regulated by RUNX1. The profiling data also showed 10-fold downregulation of phosphatidylcholine transfer protein (PCTP) gene (fold change ratio 0.09, p=0.02) in the patient compared with normal controls. PCTP regulates the intermembrane transfer of phosphatidylcholine (PC), a major plasma membrane phospholipid. Platelet PCTP expression is associated with increased platelet aggregation and calcium mobilization upon activation of protease-activated receptor 4 (PAR4) thrombin receptors in black subjects as compared to white subjects (Edelstein et al Nat Med 2013; 19:1609-16). Pharmacologic inhibition of PCTP decreased platelet aggregation in response to PAR4 agonist and siRNA knockdown of PCTP in megakaryocytic cells blunted calcium mobilization induced by PAR4 (Edelstein et al Nat Med 2013; 19:1609-16). Little is known regarding the regulation of PCTP in MKs/platelets and its role in cardiovascular events.Based on the decreased platelet PCTP expression in our patient, we pursued the hypothesis that PCTP is regulated by RUNX1 and contributes to cardiovascular events. Corrected total cellular immunofluorescence with anti-PCTP antibody showed significantly reduced platelet PCTP expression by 58% in our patient compared to a normal control. In silico analysis revealed 5 RUNX1 consensus binding sites up to ~ 1 kb of the PCTP 5’ upstream region from ATG. To assess for interaction of RUNX1 with the PCTP promoter, chromatin immunoprecipitation (ChIP) assay with anti-RUNX1 antibody was performed using human erythroid leukemia (HEL) cells treated with phorbol 12-myristate 13-acetate (PMA) for 48 hours to induce megakaryocytic transformation. The ChIP studies showed RUNX1 binding to PCTP chromatin in the regions encompassing RUNX1 binding site 1 (-345/-340), site 3 (-632/-627), and encompassing sites 4 and 5 (-974/-969, -997/-992). Electrophoretic mobility shift assay (EMSA) using PMA-treated HEL cell nuclear extracts showed RUNX1 binding to DNA probes (28-37 bp) containing site 1 (-345/-340) and both sites 4 and 5 (-974/-969, -997/-992). PCTP mRNA and protein expression were increased with RUNX1 overexpression and reduced with RUNX1 knockdown in HEL cells, indicating that PCTP is regulated by RUNX1. To assess the clinical relevance of the findings, the relationship between RUNX1 and PCTP in peripheral blood RNA, and PCTP and death or myocardial infarction (MI) events were assessed in two separate patient cohorts (n = 587 total patients) with cardiovascular disease. RUNX1 is transcribed from two alternate promoters (P1 and P2) resulting in different isoforms. In both patient cohorts, there was strong correlation between RUNX1 and PCTP expression in a promoter specific manner. RUNX1 P1 probe sets were strongly and inversely correlated with PCTP expression (p < 0.0001), while the P2 probe sets were not. PCTP expression was associated with death or MI in both patient cohorts (odds ratio 2.1, 95% CI [1.61-2.95], P-value < 0.0001) independent of age, sex, race, platelet count, and cardiovascular risk factors.Conclusions: Our results provide evidence that PCTP is regulated by RUNX1 (potentially in a promoter specific manner), and that PCTP expression is associated with death or myocardial infarction in patients with cardiovascular disease. RUNX1 regulation of PCTP may play a role in the pathogenesis of platelet-mediated cardiovascular events. DisclosuresNo relevant conflicts of interest to declare.

Passive exposure to agricultural pesticides and risk of childhood leukemia in an Italian community

Exposure to pesticides has been suggested as a risk factor for childhood leukemia, but definitive evidence on this relation and the specific pesticides involved is still not clear. We carried out a population-based case-control study in a Northern Italy community to assess the possible relation between passive exposure to agricultural pesticides and risk of acute childhood leukemia. We assessed passive pesticide exposure of 111 childhood leukemia cases and 444 matched controls by determining density and type of agricultural land use within a 100-m radius buffer around children's homes. We focused on four common crop types, arable, orchard, vineyard and vegetable, characterized by the use of specific pesticides that are potentially involved in childhood induced leukemia. The use of these pesticides was validated within the present study. We computed the odds ratios (OR) of the disease and their 95% confidence intervals (CI) according to type and density of crops around the children's homes, also taking into account traffic pollution and high-voltage power line magnetic field exposure. Childhood leukemia risk did not increase in relation with any of the crop types with the exception of arable crops, characterized by the use of 2.4-D, MCPA, glyphosate, dicamba, triazine and cypermethrin. The very few children (n=11) residing close to arable crops had an OR for childhood leukemia of 2.04 (95% CI 0.50-8.35), and such excess risk was further enhanced among children aged <5 years. Despite the null association with most crop types and the statistical imprecision of the estimates, the increased leukemia risk among children residing close to arable crops indicates the need to further investigate the involvement in disease etiology of passive exposure to herbicides and pyrethroids, though such exposure is unlikely to play a role in the vast majority of cases.

Is Toxoplasma Gondii Infection a Risk Factor for Leukemia? An Evidence-Based Meta-Analysis.

BackgroundPossible associations of parasite infection with cancer risk have recently attracted much attention. Published studies concerning the association between Toxoplasma gondii (T. gondii) infection and leukemia risk have generated inconsistent results. In the present study, we aimed to address this topic by conducting a quantitative meta-analysis.Material/MethodsRelevant publications were searched in electronic databases and eligible studies were rigorously screened and selected. Essential information was extracted and the data were pooled. Subgroup analysis on source of controls and detection target was also performed.ResultsA total of 6 studies that met the inclusion criteria were selected. The overall data show that T. gondii infection might have an association with increased leukemia risk (OR=3.05; 95%CI=1.83–5.08). Similar results were shown in the subgroups regarding source of controls and detection target.ConclusionsOur results suggest that T. gondii infection might be a risk factor for leukemia, providing new insight into the etiology of leukemia. Future studies with large sample sizes in different geographic areas are needed to confirm this conclusion.

Transcription Factor RUNX1 Regulates Pctp (Phosphatidylcholine Transfer Protein) in Platelets: A Potential Role in Regulating Platelet Function

Transcription factor (TF) mutations are increasingly recognized to play a major role in inherited platelet abnormalities. RUNX1, a critical hematopoietic TF, acts in a combinatorial manner with other TFs to regulate numerous megakaryocyte (MK)/platelet genes. Human RUNX1 haplodeficiency is associated with thrombocytopenia, numerous platelet function defects, and increased leukemia risk. We have previously described a patient with a heterozygous RUNX1 nonsense mutation in the conserved runt domain necessary for DNA binding (Sun et al Blood 2004;103;948-54). The patient's platelet abnormalities included impaired aggregation and secretion in response to multiple agonists, granule deficiency, and decreased phosphorylation of myosin light chain and pleckstrin, activation of GPIIb-IIIa, 12-HETE production, and platelet protein kinase C-θ. Transcript expression profiling of patient platelets (Sun et al, J Thromb Haemost 2007;5:146-54) showed numerous genes were significantly downregulated, including myosin light chain (MYL9), platelet factor 4 (PF4), protein kinase C-θ (PRCKQ), and 12-lipoxygenase (ALOX12); these have been shown by us to be regulated by RUNX1. The profiling data also showed 10-fold downregulation of phosphatidylcholine transfer protein (PCTP) gene (fold change ratio 0.09, p=0.02) in the patient compared with normal controls. PCTP is a member of the START (Steroidogenic Acute Regulatory Protein-Related Transfer) domain superfamily and is responsible for the intermembrane transfer of phosphatidylcholine (PC), a major plasma membrane phospholipid. Several findings indicate that PCTP is important for platelet function. PC is the main fraction of platelet phospholipids and source of arachidonic acid (AA) upon activation. Release of free AA from PC is the rate-limiting step in thromboxane production. PC is also a substrate for phospholipase D, which yields phosphatidic acid that can generate the second messenger diacylglycerol. Importantly, platelet PCTP has recently been demonstrated to have a major role in the racial differences in platelet responses - increased PCTP expression has been linked to the higher platelet aggregation and calcium mobilization induced by thrombin receptor protease-activated receptor 4 (PAR4) in blacks as compared to whites (Edelstein et al Nat Med 2013;19:1609-16). Little is known regarding the regulation of PCTP in MKs/platelets.Based on the decreased platelet PCTP expression in our patient, we pursued the hypothesis that PCTP is regulated by RUNX1. Corrected total cellular immunofluorescence with anti-PCTP antibody showed significantly reduced platelet PCTP expression by 58% in our patient compared to a normal control. In silico analysis revealed 5 RUNX1 consensus binding sites up to 995 bp of the PCTP 5' upstream region from ATG. To assess for interaction of RUNX1 with the PCTP promoter, chromatin immunoprecipitation (ChIP) assay with anti-RUNX1 antibody was performed using human erythroid leukemia (HEL) cells treated with phorbol 12-myristate 13-acetate (PMA) for 24 hours to induce megakaryocytic transformation. The ChIP studies showed RUNX1 binding to PCTP chromatin in the regions encompassing RUNX1 binding sites 1 (-232/-227) and 2 (-345/-340), at site 3 (-519/-514), and encompassing sites 4 and 5 (-861/-856, -884/-879). Electrophoretic mobility shift assay (EMSA) using PMA-treated HEL cell nuclear extracts showed RUNX1 binding to DNA probes (28-37 bp) containing site 1 (-232/-227) and both sites 4 and 5 (-861/-856, -884/-879). To assess the effect of modulating RUNX1 expression on PCTP expression, PMA-treated HEL cells were transfected with RUNX1 overexpression plasmid or siRNA. PCTP mRNA and protein expression were increased with RUNX1 overexpression and reduced with RUNX1 knockdown, suggesting that PCTP is regulated by RUNX1.Conclusions: Our results provide evidence that PCTP is a direct transcriptional target of and regulated by RUNX1, and a cogent molecular mechanism for downregulation of platelet PCTP in our patient with RUNX1 haplodeficiency. Regulation of PCTP by RUNX1 may be relevant to the platelet dysfunction in RUNX1 haplodeficiency as well as to racial differences in platelet responses linked to the differential platelet expression of PCTP. DisclosuresNo relevant conflicts of interest to declare.

Residential Exposure to Pesticide During Childhood and Childhood Cancers: A Meta-Analysis.

There is an increasing concern about chronic low-level pesticide exposure during childhood and its influence on childhood cancers. In this meta-analysis, we aimed to examine associations between residential childhood pesticide exposures and childhood cancers. We searched all observational studies published in PubMed before February 2014 and reviewed reference sections of articles derived from searches. The literature search yielded 277 studies that met inclusion criteria. Sixteen studies were included in the meta-analysis. We calculated effect sizes and 95% confidence intervals (CIs) by using a random effect model with inverse variance weights. We found that childhood exposure to indoor but not outdoor residential insecticides was associated with a significant increase in risk of childhood leukemia (odds ratio [OR] = 1.47; 95% CI, 1.26-1.72; I(2) = 30%) and childhood lymphomas (OR = 1.43; 95% CI, 1.15-1.78; I(2) = 0%). A significant increase in risk of leukemia was also associated with herbicide exposure (OR = 1.26; 95% CI, 1.10-1.44; I(2) = 0%). Also observed was a positive but not statistically significant association between childhood home pesticide or herbicide exposure and childhood brain tumors. The small number of studies included in the analysis represents a major limitation of the current analysis. Results from this meta-analysis indicated that children exposed to indoor insecticides would have a higher risk of childhood hematopoietic cancers. Additional research is needed to confirm the association between residential indoor pesticide exposures and childhood cancers. Meanwhile, preventive measures should be considered to reduce children's exposure to pesticides at home.

Germline Gene Mutation May Increase Leukemia Risk

Germline Gene Mutation May Increase Leukemia Risk

Early Occurrence of Therapy-Related Acute Myeloid Leukemia (t-AML) with Monocytic Differentiation with Trisomy 8 Cytogenetic Abnormality after Radioactive Iodine (RAI) Treatment for Papillary Thyroid Cancer

Background: Although most t-AML occurs after chemotherapy +/- radiation, exposure to radioactive substances can be implicated, as in nuclear accidents. Thyroid cancer is the most commonly endocrine malignancy. The relative risk of second primary malignancy in thyroid cancer patients is higher in those treated with RAI than those without, with a notable 2.5-fold increase risk of leukemia. The excess leukemia risk is greater in patients < 45 yrs compared with older patients. Recent reviews have attempted to characterize cytogenetic and molecular abnormalities from RAI related t-AML. We present the case of a young woman who developed AML with monocytic differentiation and Trisomy 8 cytogenetic abnormality after RAI treatment for thyroid papillary carcinoma.Case Presentation: A 29-year-old Chinese woman presented with worsening fatigue and menorrhagia over 3 months. Initial workup revealed pancytopenia (WBC 1.7, Hb 8.3, Hct 24, PLT 44, ANC 0.7). She had a history of papillary thyroid carcinoma, classic type, treated with total thyroidectomy followed by RAI ablation with 99 mCi of I-131 2 years prior. She had been without evidence of residual/recurrent disease since then. Her only home medication was Levothyroxine and had no other toxic exposure. Physical exam was unremarkable. Serology was negative for HIV, Hepatitis B or C. Peripheral smear showed decreased WBC count, few circulating blasts, atypical monocytes, and decreased platelets. Bone marrow aspiration and biopsy showed marked hypercellular marrow (100%) replaced by sheets of myeloid appearing-blasts, increased medium/large size CD68+ monoblasts with moderate basophilic vacuolated cytoplasm, as well as promonocytes comprising 90% of nucleated marrow cells. This was consistent with AML with monocytic differentiation. Flow Cytometry confirmed presence of HLA-DR, CD56, CD64, CD2, CD5, CD4, and CD11+ myeloblasts (27% of total cells) with increased CD56+ monocytes (23%). Cytogenetic analysis identified trisomy 8. Molecular testing was negative for FLT3 ITD and FLT3 TKD mutations by PCR, and negative for PML-RARA rearrangement by FISH.The patient was started on induction chemotherapy with cytarabine 100 mg/m2 daily as continuous infusion on days 1-7 + Idarubicin 12 mg/m2 daily for days 1-3 (7+3 regimen). Repeat bone marrow evaluation on day 14 revealed complete histologic and cytogenetic response. She received three cycles of consolidation with high dose cytarabine 3 g/m2. She is presently awaiting identification of a matched donor for allogeneic hematopoietic stem cell transplantation.Discussion: t-AML is a distinct subgroup of AML in 2008 WHO classification for their attributed worse outcome than their de novo counterparts with the same genetic abnormalities [except inv(16)(p13.1q22), t(16;16)(p13.1;q22) or t(15;17)(q22;q12)], suggestive of biologic differences. However, these findings are largely derived from patients who received cytotoxic treatment with topoisomerase II inhibitors, alkylating agents and/or RT. In contrast, little is known about outcome and prognosis in t-AML from RAI. We present a young woman with RAI related t-AML with monocytic differentiation and trisomy 8 after a 2-year latency who responded to standard induction and consolidation chemotherapy. To our knowledge the monocytic differentiation with Trisomy 8 was previously unreported.Retrospective studies and case series suggest that median latency of RAI related t-AML is ~ 7 yrs, in bimodal distribution peaking at 1-3 years and later at 8-10 years. 68% of t-AML from RAI have abnormal karyotype, with chromosomes 7, 5, and 8 most commonly involved, notably del 7q. FAB M2, M3, and M4 represented the vast majority of cases. Compared to patients with other t-AML, RAI-related AML tend to have significantly inferior survival. This suggests a unique mechanism of secondary primary malignancy, possibly via the Na(+)/I(-) symporter, a membrane glycoprotein that mediates active iodide uptake in thyroid and other tissues.Conclusion: t-AML from RAI is an under-recognized and under-reported form of AML, with unclear mechanism, wide-spectrum cytogenetic abnormalities and histology, undefined dose-risk ratio, and decreased survival. As the incidence of thyroid cancer increases, and utilization of RAI becomes more frequent, further investigation is needed to better characterize this unique entity, early detection and its optimal treatment. DisclosuresNo relevant conflicts of interest to declare.

French nuclear power plants and childhood leukemia.

The Geocap Study described by Sermage-Faure et al. (2012) suggested to them “a possible excess risk of AL [childhood acute leukemia] in the close vicinity of French NPPs [nuclear power plants] in 2002–2007”. The abstract contains general results of two analyses: the nationwide Geocap case-control study showing the odds ratio of cancer incidence OR = 1.9 (1.0–3.3, 95% confidence interval [CI]) and a concomitant study with standardized incidence ratio (SIR) = 1.9 (1.0–3.2, 95% CI). However, we provide evidence that this hypothetical risk increase is likely a statistical fluctuation. In addition, the data are subject to confounding factors that were not addressed. The putative increase in leukemia risk therefore cannot be justifiably attributed to very small radiation doses associated with the operation of the NPPs. First, the authors have not one datum in Table 2 (Sermage-Faure et al. 2012) that shows a statistically significant increase in cancer risk, whether for children under 5 or under 15 years of age, in either the interval 1990–2001 or 2002–2007. Only by data dredging and subdividing the numbers into smaller time intervals and other discriminatory indices in Table 4 (Sermage-Faure et al. 2012), can they produce a few showing statistical significance. But then, the numbers of children included in each time interval are small. Second, the results in the abstract are based on only 14 cancer cases near 19 NPPs. Fourteen cases are too few for a clinically significant result. Fourteen cases near 19 NPPs are on average 0.7 cases per NPP. Third, neither any confounding factor nor individual history of the children (especially their migrations) was taken into consideration. These omissions and the mentioned small-sample-size-related statistical problems invalidate the claimed association of cancer risk with NPP proximity. Additional weak points of the analysis were diligently mentioned by the authors (Sermage-Faure et al. 2012). First, no correlation was found between cancer cases and radioactive releases from NPPs. Second, similar French investigations several years earlier failed to find an increase in risk (White-Koning et al. 2004; Evrard et al. 2006; Laurier et al. 2008). And the evaluation over a wider time period (1990–2007) did not show a statistically significant risk increase. Third, total accumulated doses over the time period 2002–2007 were in the range of microsieverts – several orders of magnitude lower than the variations in natural background radiation. Fourth, lower doses were received by children living up to 5 km from the NPP, where the risk was estimated to be higher, while no risk increase was found among children who received the highest doses. These four weaknesses alone should have been sufficient to invalidate any claimed association between NPP operation and cancer, without the three points raised in this Letter. One can add also that despite the authors’ reluctance to unambiguously relate the leukemia incidence to the NPP emissions, they nevertheless suggest that leukemia is a consequence of radiation exposure from NPP operation. We point out in the present Letter why this suggestion is not justified. Attribution of an excess risk of cancers to nearby NPPs is a well known practice, even though many independent studies, such as COMARE (2011), CANUPIS (Spycher et al. 2011) or RADICON (2013), have demonstrated no correlation between radiation exposures around NPPs and cancer incidence. Observed increases can be attributed to population mixing, as pointed out in the most recent extensive review of childhood leukemia around NPPs (Janiak 2014). The population mixing hypothesis considered involves “the influx of outside workers to rural regions where nuclear installations are being set up and where local people are not immune to pathogens brought along with the incomers” (Janiak 2014). The Geocap Study (Sermage-Faure et al. 2012) is one of many studies on cancer risk around NPPs. The presented conclusions implicitly blame NPP-related, low-dose-radiation exposures for increased cancer risk. The “call for investigation for potential risk factors related to the vicinity of NPP” (Sermage-Faure et al. 2012) should be seriously questioned because such studies will lack statistical power for demonstrating any change (increase or decrease) in risk. In addition, such studies can promote potentially-harmful radiophobia (Jaworowski 2010; Scott 2011; Orient 2014), thereby making it difficult to communicate accurate information to the public on the health effects of radiation exposure, especially in the event of an actual radiological emergency (Allison 2009; Sanders 2010). The previous version of this Letter was submitted to the International Journal of Cancer. In his reply, the Editor stated that our remarks would not interest the journal’s readers.