Risk Of Acute Leukemia Research Articles

GSTT1 Null Genotype and Susceptibility to Children Acute Leukemia in Chinese Population: Evidence from a Meta-Analysis

Objectives:Increasing number of studies has focused on studying the relationship between glutathione S-transferase T1 polymorphism and children acute leukemia, among which discrepancies have risen. The aim of this study is to provide a more exact assessment of glutathione S-transferase T1 polymorphism and children acute leukemia among certain Chinese population.Methods:Studies were identified using PubMed, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure and Chinese Biology Medicine from beginning to July 2018. The strength of association was quantified by pooling odds ratios and 95% confidence intervals using fixed-effect or random-effect model according to the heterogeneity.Results:Overall, a positive relationship was found in null genotype of glutathione S-transferase T1 polymorphism on the risk of childhood acute leukemia among all Chinese populations (odds ratios: 1.52; 95% confidence intervals = 1.19-1.94). Similarly, consistent results were found in subgroup of Southern China (odds ratios: 1.48; 95% confidence intervals: 1.08-2.02), Northern China (odds ratios: 1.59; 95% confidence intervals: 1.09-2.33), acute lymphoblastic leukemia (odds ratios: 1.61; 95% confidence intervals: 1.19-2.17), “age > 18 years” (odds ratios: 1.59; 95% confidence intervals: 1.09-2.33), “age < 18 years” (odds ratios: 1.48; 95% confidence intervals: 1.08-2.02), and population-based studies (odds ratios: 1.60; 95% confidence intervals: 1.16-2.20).Conclusions:Collectively, finding from the current study indicated that GSTT1 null polymorphism may be susceptible on childhood acute leukemia among Chinese.

Maternal prenatal exposure to environmental factors and risk of childhood acute lymphocytic leukemia: A hospital-based case-control study in China

Objective: To investigate an association between maternal prenatal exposure to several environmental factors and risk of childhood acute lymphocytic leukemia (ALL), and the possible interactions in the Chinese population.Methods: 345 cases with ALL and their 1:1 age, gender, residence region matched controls aged 0–15 years were recruited from four hospitals in Henan Province from 2014 to 2016. Information was collected by interviews using a questionnaire. Unconditional logistic regression adjusted for age, gender, residence region and relevant confounders was carried out to generate the odds ratios (ORs) and 95% confidence intervals (CIs).Results: Our data indicate that maternal prenatal exposure to interior housing renovation (adjusted OR: 2.98, 95% CI: 1.51–5.86) or pesticides (adjusted OR: 1.48, 95% CI: 1.67–2.28) increased the risk of childhood ALL. Various subgroup analyses stratified by child's gender, age at diagnosis and other factors also supported these results. However, no interaction was detected between exposure to internal housing renovation and pesticides using an additive model. No significant links between maternal exposures to, environmental tobacco smoking (ETS), antipyretic analgesia intake, or viral infectious diseases with risk of ALL were detected.Conclusion: Findings in our study are in line with the existing literatures, which support the hypothesis that maternal prenatal exposure to interior housing renovation and pesticides are risk factors for childhood ALL. Notably, we found no interaction between these two risk factors, these findings may inform prevention and early detection strategies.

Functional and Molecular Consequences of Trisomy 21 on Human Fetal Hematopoiesis

Children with Down Syndrome (DS) are at 150-fold increased risk of developing acute megakaryoblastic leukemia (ML-DS) and 33-fold increased risk of acute B-lymphoblastic leukemia. The multistep pathogenesis of DS - associated pre-leukemia and subsequent progression to ML-DS is among the most well characterized human blood malignancies. Trisomy 21 fetal liver (FL) provides a tractable model for dissecting T21-mediated pre-leukemic changes in human HSPC. Using a recently published (Notta, F. et. al., Science 2016) enhanced sorting scheme for human blood progenitors and paired normal disomic and trisomic human FL samples, we sought a more thorough understanding of the molecular and functional perturbations associated with T21 in human FL hematopoiesis by: 1) assessing the proportional frequency/absolute numbers of 12 normal and T21 FL HSPC populations, 2) examining clonal, proliferative and lineage output using single cell stroma-based myelo-erythroid (ME) and myelo-lymphoid (ML) differentiation assays, 3) performing RNA seq and ATAC seq to elucidate variations in gene expression and epigenetic alterations, 4) and generating long-term clonal xenografts from highly purified normal and T21 FL HSC followed by secondary transplantation to uncover alterations in HSC frequency, lineage output and progenitor hierarchy.Flow cytometry was performed on 4 sets of paired, gestational stage matched disomic and trisomic human fetal liver CD34+ HSPC samples to assess changes in the proportional frequency/absolute numbers of 12 HSCP populations. Our results reveal that the T21 FL hierarchy exhibits increased frequencies of HSC, LMPP, MPP F2/F3, CMP F3 and MEP F3 populations and concomitantly decreased MPP F1, CMP F1, MEP F1 and GMP populations. To assess T21-induced functional changes at the clonal level, we utilized single cell stroma-based differentiation assays. In ME assays, we observed increased Mk lineage output while oligopotent lineage output (M/E/Mk) was found to be skewed into the CD34+CD38+ compartment. Single cell ML assays demonstrated a loss of B lineage differentiation potential and greatly reduced NK lineage output that resulted in a complete loss of oligopotent clones (B/NK/M) in HSC, MPP F1 and LMPP. Despite observing increased numbers of immunophenotypic HSC in T21 FL samples, in vivo LDA xenotransplantation of highly purified CD34+CD38-CD90+CD45RA-CD49f+ HSC showed no change in the frequency of functional T21 FL HSC. Compared to control, T21 HSC produced smaller hCD45+ grafts with increased CD33+ myeloid, CD41+ Mk and platelet frequencies and reduced GlyA+ erythroid frequency. Furthermore, T21 grafts demonstrated an inverted CD14+ monocyte/CD66b+ granulocyte ratio with almost complete loss of CD66b+CD16+CD49d- neutrophils. Initial RNA seq results from highly purified disomic and trisomic HSC and MPP reveal aberrant expression of genes from pathways not previously implicated in T21 associated malignancies. These data suggest that T21 induces relatively consistent alterations in population frequency across the FL blood progenitor hierarchy. Furthermore, our data suggests that T21 FL HSC are biased toward E, M, Mk lineage fates at the expense of B, T, NK and neutrophil fates. Overall, our work provides unique and previously unrecognized insights into the pathogenesis of DS-associated leukemia. DisclosuresNo relevant conflicts of interest to declare.

Modeling the Initiation and Evolution of Down Syndrome Associated Leukemia Using CRISPR/Cas9

Children with Down syndrome, also known as trisomy 21, have a significantly increased risk of childhood acute leukemia in the first few years after birth. The acute leukemia phase is preceded with a transient pre-leukemia phase in newborns, which is characterized by a clonal proliferation of immature megakaryocytes carrying somatic mutations in the GATA binding protein 1 (GATA1). These acquired GATA1 mutations lead to the expression of the GATA1 short isoform and prevent the expression of the GATA1 long isoform. The pre-leukemia undergoes spontaneous remission within the first few months after birth. In 20% - 30% of the cases, children progress to acute myeloid leukemia (AML) after remission, in which the pre-leukemic clone acquires additional mutations, such as in genes of the cohesin complex. It is hypothesized that this represents a multi-step process of leukemogenesis with three distinct genetic events: trisomy 21, GATA1 mutation and additional tertiary mutations.Here, we wanted to model the initiation and evolution of Down syndrome associated pre-leukemia and AML by employing CRISPR/Cas9. For this, we developed a CRISPR system that allows the precise manipulation of human hematopoietic stem and progenitor cells using electroporation of Cas9 protein and chemically synthesized gRNAs. We utilized human cord blood and fetal liver as a source of hematopoietic stem and progenitor cells (HSPCs).We were able to force the re-assignment of GATA1 isoforms to either the short or long isoform using CRISPR/Cas9 in purified hematopoietic stem cells (HSCs), multi-potent progenitors (MPPs), common myeloid progenitor (CMPs) and megakaryocyte/erythrocyte progenitors (MEPs). For each of these populations, we assayed their differentiation potential in single cell in vitro assays. In short, after electroporation and CRISPR/Cas9 mediated re-assignment to either the GATA1 short or long isoform, single cells were deposited onto MS5 stromal cells and were grown for 16-17 days in erythro-myeloid differentiation media. Individual colonies were analyzed by flow cytometry for their differentiation potential and genotyped to confirm CRISPR/Cas9 mediated GATA1 short or long isoform re-assignment. Overall, we were able to observe cell type specific and isoform specific effects on differentiation. For example, re-assignment to the GATA1 short isoform restricted erythroid differentiation and promoted megakaryocytic output in HSCs and MPPs. This effect was both seen when cord blood or fetal liver was used as the source of HSPCs. To confirm the role of the short isoform of GATA1, we transplanted HSCs with GATA1 short in a clonal fashion into immunocompromised mice and after 20 weeks observed grafts with high megakaryocytic output compared to control HSCs. Similarly, GlyA+ erythroid output was significantly decreased compared to transplanted control HSCs.In summary, this CRISPR/Cas9 system allows us to investigate the differentiation potential of single cells that are restricted to the endogenous expression of either the short or long isoform of GATA1. Future work will include the utilization of trisomy 21 HSCPs and the introduction of tertiary mutations, such as loss of function of STAG2, to potentially progress the model to an acute leukemia phase. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Investigating Patient Characteristics and Outcomes of Myelofibrosis Patients with Hyperleukocytosis

Background: Primary myelofibrosis (PMF) is a myeloproliferative neoplasm that is marked by bone marrow fibrosis, cytopenias, extramedullary hematopoiesis, and a increased risk of acute leukemia. Leukocytosis is frequently seen and a white blood cell count (WBC) > 25,000/uL has been shown to convey an inferior prognosis. Rarely, patients develop severe leukocytosis (defined as WBC > 50,000/uL) either at presentation or during the course of their disease. Genomic characterization, management, and outcomes of these patients are not well defined. In this study, we aimed to further characterize PMF patients with severe leukocytosis and assess their clinical outcomes.Methods: We retrospectively reviewed PMF patients who presented to our institution between 2001 and 2018. We included patients who developed a WBC count > 50K at any time during their clinical course. Patients who developed acute myelogenous leukemia (AML) were censored at the time of disease diagnosis. Overall survival (OS) defined from first date that WBC documented as > 50K.Results: Among 493 PMF patients treated at our institution, 71 (14.4%) developed severe leukocytosis during the course of their disease. Ten (14%) had severe leukocytosis at the time of diagnosis and 30 (42%) developed it within 1 year of diagnosis and 40 (56%) developed it more than 1 year after diagnosis. Eight (11.3%) patients demonstrated peripheral blast percentage > 10% blasts at the time severe leukocytosis first documented.Compared to patients who did not develop severe leukocytosis, those with severe leukocytosis had an increased frequency of EZH2 (p < 0.001), RAS (p < 0.001), and KIT (p = 0.04) mutations. ASXL1 mutations were seen in a similar proportion of patients (p = 0.41). A similar proportion of patients were high risk by GIPSS (26% v 24%) prognostic model.From the time development of severe leukocytosis, the median overall survival (mOS) was 13.3 months. Median OS from diagnosis was significantly shorter for patients who developed severe leukocytosis (35.4 mo v 63.5 mo; p = 0.02) compared to those that did not. Eleven (15%) patients with severe leukocytosis developed AML compared to 38 (9%) patients who did not develop severe leukocytosis (p = 0.13). Median time to development of AML was 13.3 months from time of severe leukocytosis.At development of severe leukocytosis, 12 patients (17%) received hydrea (mOS 14.0 months) and 9 patients (13%) received ruxolitinib (mOS 21.2 months). The remaining cohort which either received no documented treatment, an alternative treatment or unknown treatment had a mOS of 5.3 months. This was not statistically significant. Ten patients (14%) ultimately underwent allogeneic stem cell transplantation after the development of hyperleukocytosis.Conclusion: Severe leukocytosis occurs rarely in primary myelofibrosis. RAS, KIT, and EZH2 mutations are enriched in these patients. Management strategies in these patients is varied and outcomes are poor. Further studies assessing the benefit of cytoreductive therapies in this population should be performed. [Display omitted] DisclosuresSallman:Celgene: Research Funding, Speakers Bureau. Sweet:BMS: Honoraria; Astellas: Consultancy; Jazz: Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Jazz: Speakers Bureau; Phizer: Consultancy; BMS: Honoraria; Celgene: Honoraria, Speakers Bureau; Astellas: Consultancy; Agios: Consultancy; Phizer: Consultancy; Celgene: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy. List:Celgene: Research Funding. Komrokji:Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Kuykendall:Janssen: Consultancy; Celgene: Honoraria.

Maternal exposure to gasoline and exhaust increases the risk of childhood leukaemia in offspring \u2013 a prospective study in the Norwegian Mother and Child Cohort Study

BackgroundIn the prospective population-based Norwegian Mother and Child Cohort Study (MoBa), comprising 113 754 offspring, we investigated the association between parental exposure to “gasoline or exhaust”, as a proxy for benzene exposure, and childhood leukaemia.MethodsAround gestational week 17, mothers and fathers responded to a questionnaire on exposure to various agents during the last 6 months and 6 months pre-conception, respectively. Benzene exposure was assessed through self-reported exposure to “gasoline or exhaust”. Cases of childhood leukaemia (n = 70) were identified through linkage with the Cancer Registry of Norway. Risk was estimated by hazard ratios (HRs) with 95% confidence intervals (95%CI), comparing offspring from exposed and unexposed parents using a Cox regression model.ResultsMaternal exposure to "gasoline or exhaust" was associated with an increased risk of childhood leukaemia (HR = 2.59; 95%CI: 1.03, 6.48) and acute lymphatic leukaemia (HR = 2.71; 95%CI: 0.97, 7.58). There was an increasing risk for higher exposure (p value for trend = 0.032 and 0.027). The association did not change after adjustment for maternal smoking.ConclusionIn spite of rather few cases, the findings in this prospective study, with the exposure metric defined a priori, support previous observations relating maternal exposure to benzene from gasoline and other petroleum-derived sources and the subsequent development of childhood leukaemia in the offspring.

Characteristics and Predictors for Secondary Leukemia and Myelodysplastic Syndrome in Ewing and Osteosarcoma Survivors

Long-term survivors of Ewing sarcoma (ES) and osteosarcoma may be at risk for therapy-related acute leukemia or myelodysplastic syndrome (t-AL/MDS). We retrospectively reviewed the clinicopathologic characteristics of 1071 patients with osteosarcoma (n=757) and ES (n=314) who were treated between 1985 and 2014. Multivariable competing risk analysis was used to analyze predictors of t-AL/MDS, including a radiation dose (≥55.8Gy vs <55.8Gy)×disease site (pelvis/spine vs other) interaction term. A supplemental nested case-control study was conducted to assess the association between cumulative chemotherapy dose and t-AL/MDS. The median follow-up for surviving patients was 97months (range, 0.03-380). Twenty patients developed t-AL/MDS, all of whom received chemotherapy and 15 of whom were treated with radiation therapy. Radiation therapy to ≥55.8Gy was associated with development of t-AL/MDS (adjusted hazard ratio, 2.89; 95% confidence interval [CI], 1.23-6.80; P=.015), and there was a significant radiation dose×disease site interaction term (adjusted hazard ratio, 6.70; 95% CI, 2.71-16.53; Pinteraction<.001). The 5-year cumulative incidence of t-AL/MDS in patients receiving ≥55.8Gy radiation therapy to the pelvis or spine was 5.0% (95% CI,0.9-14.9) for osteosarcoma and 10.7% for ES (95% CI, 3.3-23.2). In our nested case-control study, cumulative doses of ifosfamide and etoposide were associated with development of t-AL/MDS. Patients with osteosarcoma and ES receiving ≥55.8Gy of radiation therapy to the pelvis or spine appear to be at increased risk for t-AL/MDS. Treatment with high cumulative doses of chemotherapy may further augment this risk.

Breastfeeding and Its Associated Risk in Children with Acute Leukemia: A Retrospective Study

AbstractAim: This study aims to study the protective risk association between the breastfeeding pattern and acute leukemia in children. Materials and Methods: Retrospective study in Kidwai Institute of Oncology, Bangalore. One hundred and twenty cases and 120 controls were enrolled during April 1, 2015–July 31, 2015. Cases include children diagnosed with acute leukemia either ALL or AML, between the age group of 1–15 years, with an elderly sibling and availability of biologic mother for collecting data regarding breastfeeding pattern. Controls include the elder sibling of the cases, children on compassionate care toward end of life, and also whose mother denied to give consent were excluded from the study. Statistical Analysis Used: Pearson Chi-square test, conditional logistic regression models, and Fischer's extract tests were used to assess the association between breastfeeding patterns and risk of acute leukemia. Results:: The acute leukemia cases and controls were similar with respect to sex, birthweight, maternal education, and socioeconomic status. Frequency of ever breastfeeding was same 99% in both cases and controls, odds ratio of ever breastfed to never breastfed (odds ratio = 1;95% confidence interval = 0.13–7.21) was not associated with risk of acute leukemia. Exclusive breastfeeding ≤2, 2–4 and 4–6 months as compared to exclusive breastfeeding beyond 6 months were associated with significant risk of acute leukemia and the P value trend is 0.0026. Similarly, continued breastfeeding till 1 year of age as compared to beyond 1 year was also associated with highly significant risk of acute leukemia with P value trend of 0.0001. Whereas continued breastfeeding till 2 years as compared to beyond 2 years was not associated with any risk of acute leukemia with P value trend of 0.3433. Conclusion: Significant association between breastfeeding and risk of acute leukemia was observed.

Abstract 450: Obesity favours leukemogenesis through enhanced preleukemic stem cell self renewal via polyunsaturated fatty acid-dependent ER stress relief

Abstract Obesity increases risk for multiple tumors, but impact on leukemia and its underlying molecular mechanism are poorly understood. Studies from our group and others showed that risk and outcome of Acute Promyelocytic Leukemia (APL) are more strongly associated with obesity than other hematological neoplasms. Intriguingly, in 2 independent cohorts (Italian and TCGA), obesity was associated with ~4 fold higher incidence of internal tandem duplications of the leukemogenic kinase FLT3 (FLT3-ITD), the first example of obesity-associated genetic alterations in cancer (unpublished). Here we propose a molecular mechanisms underlying obesity-associated leukemogenesis through our studies in murine models. Exposure to High fat Diet (HFD), an established model of obesity-related pathology, strongly accelerated disease onset and mortality in 3 murine models of hematological cancer: PML-RARa knockin (PRKI), developing an APL-mimicking disease; FLT3ITD knockin (FIKI) developing myeloproliferation; a new double PRKI-FIKI knockin mouse, developing APL-like disease but, surprisingly, with delayed latency compared to PRKI, presumably due to the known exhaustion of hematopoietic stem cells (HSC) associated with FLT3ITD. Preleukemic HSCs from HFD PRKI mice showed increased DNA damage in Comet assays, but surprisingly this was not associated with increased mutational load as revealed by a novel whole genome sequencing-based method. Instead, HSCs derived from HFD PRKI mice showed enhanced self-renewal in in vitro replating assays. Similarly, in the FIKI model we observed enhanced engraftment in serial competitive transplantation experiments in HFD-fed recipients. Delving more deeply in the molecular mechanisms, through bioinformatic analysis of RNAseq data from the TCGA we found upregulation of the linoleic acid (LA) pathway in obese APL patients. LA is the richest fatty acid in HFD and in many western diets, thus a likely candidate for mediating HFD activity. LA significantly enhanced PRKI serial replating efficiency; this was abolished by pharmacologically blocking LA metabolism through a 5-lipoxygenase inhibitor or its transcriptional effects through a PPARd inhibitor. In the FIKI model and in a FLT3ITD-inducible cell line, we revealed a previously unappreciated induction of ER stress by FLT3ITD, likely to underlie FLT3ITD-induced HSC exhaustion. HFD (in vivo) and LA (in vitro) relieved FLT3ITD-induced ER stress, as revealed by the attenuation of markers of adaptive response to ER stress (Unfolded Protein Response and RNA IRE1-dependent RNA decay). In conclusion, our study suggests a novel and somewhat counterinuitive model for obesity-associated cancerogenesis: rather than inducing cellular stress, HFD-induced obesity enhances the self-renewal of preleukemic stem cells through LA-mediated alleviation of oncogene-induced proteotoxic stress Citation Format: Luca Mazzarella, Paolo Falvo, Annagiulia Sanarico, Elena Gatti, Piergiuseppe Pelicci. Obesity favours leukemogenesis through enhanced preleukemic stem cell self renewal via polyunsaturated fatty acid-dependent ER stress relief [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 450.

T-cell Non-Hodgkin lymphoma associated with myelodysplasia: A case report in a child

Myelodysplastic syndrome (MDS) is a clonal bone marrow disease characterized by ineffective erythropoiesis. MDS patients have cytopenia. The risk of acute leukemia, and particularly of acute myeloblastic leukemia (AML), is the most important characteristic of the disease. Myelodysplasia associated with NHL has been rarely described in the literature. This is suggested to be due to the defect in the immune system, an up-regulation of some cytokines, and a common molecular origin. In this case report article, we reported a 7-year-old pediatric NHL case with a normal karyotype and myelodysplasia in the bone marrow and discussed the pathogenesis of the association of NHL and myelodysplasia.

A greater birthweight increases the risk of acute leukemias in Mexican children-experience from the Mexican Interinstitutional Group for the Identification of the Causes of Childhood Leukemia (MIGICCL).

In Mexico, due to the high rates of diabetes, overweight, and obesity, there has also been noted an increased newborn weight, which may be contributing to the elevated incidence rate of childhood acute leukemia (AL). We conducted a case–control study in public hospitals of Mexico City aimed to know whether a greater weight at birth is associated with a higher risk of developing leukemia. We included incident cases with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) diagnosed between 2010 and 2015. Controls were frequency‐matched to the cases by age, sex, and health institution. Logistic regression analysis was performed adjusting risks by child's sex, overcrowding index, birth order, and mother's age at the time of pregnancy. Adjusted odds ratios (aORs) and 95% confidence intervals were calculated. A total of 1455 cases and 1455 controls were included. An evident association between ALL and child's birthweight ≥2500 g was found (aOR 2.06; 95% CI: 1.59, 2.66) and also, in those with birthweight ≥3500 g (aOR 1.19; 95% CI: 1.00, 1.41). In AML patients with birthweight ≥2500 g and ≥3500 g, an aOR of 1.77 (95% CI: 1.07, 2.94) and 1.42 (95% CI: 1.03–1.95) was observed, respectively. No association was noticed with either type of AL and a birthweight ≥4000 g. To sum up, we found a moderate association between not having a low birthweight and an increased risk of acute leukemias. Birthweight ≥3500 g was also a risk factor for both types of leukemia. This suggests that a greater birthweight may increase the risk of acute leukemias in Mexican children.

Comparison of induction therapy in non-high risk acute promyelocytic leukemia with arsenic trioxide or in combination with ATRA

BackgroundAcute promyelocytic leukemia (APL) is a curable form of acute myeloid leukemia; in recent years, the use of new treatment strategies, such as combination therapy, have led to improved APL outcomes. Here, outcomes of patients treated with a combination of arsenic trioxide (ATO) and all-trans-retinoic acid (ATRA) are compared against patients treated with single ATO therapy. Patients and methodsIn total, 67 patients with non-high-risk APL were evaluated. A group of 30 patients received ATO, and another group of 37 patients received ATO plus ATRA. ATO infusion at a dose of 0.15 mg/kg/day was continued till complete remission was achieved or till 60 days of consumption, and after 28 days of rest, second ATO course was initiated for 28 days as consolidation. Four courses separated by 28-day rest were planned. In the second group, 45 mg/m2/day ATRA was added to ATO protocol. ResultsAll patients except one in the ATO group and all patients in the ATO plus ATRA group were alive after a median follow-up of 18 and 17 months, respectively; 2.5-year overall survival in the ATO group was 86% (p-value = .32). Five patients in the ATO group experienced relapse, and 2.5-year leukemia-free survival in this group was 60%. No relapse occurred in the ATO plus ATRA group (p-value = .01). Differences in the mean of white blood cell (p-value = .67), platelet (p-value = .15), liver (p-value = .37), and renal (p-value = .95) dysfunctions were not significant. ConclusionAlthough ATO has been considered a first-line therapy in patients with APL, several studies have reported improved outcomes with a combination of ATO plus ATRA. This study demonstrated a significant decrease in relapse with this combination compared with single ATO therapy and supported the importance of ATRA in APL treatment.

Correlation between survivin polymorphism and acute leukemia of children.

The correlation between the variations in the polymorphic sites of survivin, rs9904341C/G and rs8073069C/G, and the pathogenesis of acute leukemia, as well as the guiding significance in clinical practice were investigated. We enrolled a total of 182 children with acute leukemia and 200 healthy children as the subjects. In accordance with the case-control method, the polymerase chain reaction was carried out for genetic typing of the two polymorphic sites, rs9904341C/G and rs8073069C/G. In the case group and the healthy group, the frequencies of C and G alleles in rs9904341C/G of survivin were 59.3 and 41.7%, and 46.7 and 50.3%, respectively, and the pairwise comparison showed statistically significant differences (P=0.008). Additionally, the frequencies of genotypes, C/C, C/G and G/G, were 38.5 and 41.7%; 19.8 and 26.5%; 16.5 and 27.0% in the case group and the healthy group, respectively, and the differences in comparisons showed statistical significance (P=0.033). The genotype frequency of C/C in the case group was 38.5%, significantly higher than that in the healthy group (26.5%). Compared with C/C, the risk coefficient of leukemia in patients with genotypes of C/G or G/G was significantly decreased. In the case group and the healthy group, the frequencies of C and G alleles in rs8073069C/G of survivin were 30.5 and 69.5%; 27.7 and 72.3%, respectively, and the pairwise comparison showed no statistically significant differences (P=0.404). Additionally, the frequencies of genotypes, C/C, C/G and G/G, were 11 and 39.0%; 50.0 and 9.0%; 37.5 and 53.5% in the case group and the healthy group, respectively, and the differences in comparisons showed no statistical significance (P=0.62). Compared with the genotype of C/C, we found that the risk of leukemia was not affected in patients with genotypes of C/G and G/G. In conclusion, the SNP of rs9904341C/G in survivin may be correlated with the risk of acute leukemia, and compared with C/C genotype, patients with C/G or G/G may have a decreased risk of acute leukemia. In survivin, rs8073069C/G may have no correlation with the risk of acute leukemia.

Comprehensive Association Analysis of 30 Single Nucleotide Polymorphisms Related with Metabolic Syndrome on Cancer Susceptibility in Japanese Population: A Case – Control Study

Single nucleotide polymorphisms (SNPs) related with metabolic syndrome may influence cancer. Our study aimed to replicate association studies of 30 selected polymorphisms pertaining to 21 genes and cancer phenotypes in Japanese elderly population. All polymorphisms were determined by genotyping on the samples collected from 1503 consecutive autopsy cases registered in the Japanese SNPs for geriatric research (JGSNP) data base. Current study consisted of 807 (54%) males and 696 (46%) females with a mean age of 80.3 ± 8.9 years. Number of males with cancer was 520 (57%) and females 398 (43%) in total of 918 (61%) cancer present cases and 585 (39%) controls without cancer. Our pathological cancer phenotypes consisted of gastric cancer (n=178), lung cancer (n=163), colorectal (n=137) and others. Our results indicated that rs1800470 (P10L) located TGFβI gene has significant association with overall cancer (CT: CC adjusted odds ratio (OR) 95% confidence interval (95% CI)=1.386 (1.017 – 1.888), p=0.007, TT: CC adjusted OR (95% CI)=1.438 (1.106 – 1.870), p=0.039, CT + TT: CC, adjusted OR (95% CI)=1.421 (1.111 – 1.816), p=0.005), and also with lung cancer ( CT + TT: CC adjusted OR (95% CI)=1.562 (1.024 – 2.383), p=0.039) in all subjects. We also found rs2243250 located in IL4 gene is associated with elevated risk of acute leukemia (TT + CT: CC adjusted OR (95% CI)=2.286 (1.243 – 4.206), p = 0.008). Furthermore, rs2077647 on ESRI gene was associated with decreased risk of acute leukemia (GG + AG: AA, adjusted OR (95% CI)=0.516 (0.319 – 0.835), p=0.007). We found that rs1800470, rs2243250 and rs2077647 polymorphisms may influence cancer in Japanese elderly population. Our study warrants further confirmations with larger samples.

Parental Occupational Exposures and Risk of Childhood Acute Leukemia.

Introduction:Acute leukemia, accounting for 20% of all cancers diagnosed in individuals younger than 19 years old, is the most prevalent childhood malignancy. Among environmental risk factors, parental occupational exposures have attracted scientific interest as potential predisposing factors for childhood leukemia. The role of parental occupational exposure to social contacts, harmful chemicals, electromagnetic fields and ionizing radiation has been investigated with conflicting and inconsistent results.Aim:A case-control study aiming to assess the association between parental occupational exposures to social contacts, chemicals and electromagnetic fields and the risk of offspring acute leukemia.Material and Methods:108 children with acute leukemia and equal number of matched controls were included. Data on parental occupations before conception, during pregnancy, during breastfeeding and after birth, and on potential risk factors was recorded. Associations between parental exposure and risk of childhood leukemia were estimated.Results:Parental occupational exposure during the four periods of exposure was not associated with childhood leukemia. High birth weight and family history of cancer were associated with the development of childhood acute leukemia. A weak association of maternal medication use during pregnancy and leukemia risk emerged.Conclusions:Since the causative factors of childhood leukemia remain unknown, further investigation is mandatory for the reduction of disease burden.

Association of Acute Myeloid Leukemia and Systemic Lupus Erythematosus: A Case Report

Systemic lupus erythematosus is an autoimmune Inflammatory disease that can affect multiple systems and organs of the body including skin, kidneys, lungs, joints and nervous system.Some previous studies up light thatSLE was associated with increased risk of Acute leukemia (SIR = 2.3). The incidence ofthe association of AMLand SLE is not known but there are few case reports in literature. The aim of this report was to up light the difficulties wich occurred in the diagnosis and the management of acute myeloid leukemia in patient with systemic lupus erythematosus. Patient, 43 years old, diabetic treat withinsulin, wichsister is followed for Behcet's disease, was admited for AML with trisomy of chromosome 4 and 8 and thrombophlebitis of the superior sagittal sinus, Chest CT-Scan showed minimal bilateral pleural effusion. She was treated according to Morocco National protocol AML-MA-2011. CT-Scan was done atday 12 ofchemotherapy and noticedthe persistance of the minimal bilateral pleural effusion.At day 19 the patient presentedmalar rash, and right axillary adenitis. The biopsy of the adenitis show the presence of LE cells. According to internal physician recommendations we add steroids to the treatement. The cough and fever deasapear. The CT-scan for control was normal after two weeks of steroids. Patient is in complete remission after induction I. After a following-up of five months, the patient still well,but present severy infections during chemotherapy cycles and a bad tolerance for the treatement. The association SLE-AML is rare. The diagnosis of the association SLE-AML is difficult. It is management is also difficult according to commorbidity, severy infectious because of dicline of immunity, and less tolerance to AML chemotherapy.

Secondary Acute Leukemia in Sarcoma Patients: A Population-Based Study

Tocompare rates of secondary acute leukemia between sarcoma patients and the general population, using data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) registry, and to examine whether various patient, tumor, and treatment factors were associated with development of a secondary acute leukemia. Patients with a primary diagnosis of connective tissue malignancy between 1973 and 2008 in the SEER database were included. Multivariable competing risk analysis was used to determine risk factors associated with subsequent development of acute leukemia. Using observed-to-expected ratios, we compared incidence rates of secondary acute leukemia between sarcoma patients and the general population. A total of 72,945 patients were identified, with median follow-up of 131months. On multivariable competing risk analysis, factors associated with increased risk of secondary acute leukemia included receipt of radiation therapy (hazard ratio [HR] 1.67, P=.02), distant disease (HR 2.67, P=.004), male gender (HR 1.53, P=.03), year of diagnosis (HR 0.98, P=.049), and Ewing sarcoma histology (HR 9.95, P < .0001) and osteosarcoma histology (HR 5.06, P=.0001). The observed-to-expected ratio for development of a secondary acute leukemia was 3.67 (95% confidence interval [CI] 1.95-6.28), 3.41 (95% CI 2.73-4.20), and 1.6 (95% CI 1.38-8.19) for acute lymphocytic leukemia, acute myeloid leukemia, and acute monocytic leukemia, respectively. The 10-year cumulative incidence of secondary acute leukemia for patients who did and did receive radiation therapy was 0.3% versus 0.1% (P=.02). Patients treated for sarcoma, in particular those with Ewing sarcoma and osteosarcoma histology, seem to have a higher incidence of secondary acute leukemia as compared with the general population. Treatment factors including radiation therapy and chemotherapy seem to play a role in this increased risk, although the absolute incidence nevertheless remains very small.

Association between expression of plasma miRNA and the risk of childhood acute lymphocytic leukemia

Objective: To investigate the characteristics of distribution and expression profiles of plasma miRNA in childhood acute lymphocytic leukemia (cALL) patients; the association between cALL incidence risk and plasma miRNA levels; the feasibility of plasma miRNA serving as cALL diagnostic biomarker. Methods: A total of 111 pairs of newly diagnosed cALL patients and patients with fractures were collected from Shenzhen Children's Hospital, China, between January 2015 and November 2016. Age and sex of the cases and controls were 1∶ 1 matched and LNA(TM) miRNA microarray was performed using 4 pairs of cALL and controls selected from the sample population. The expression level of miRNA was validated by real time quantitative PCR. Conditional logistic regression analysis was applied to evaluate the association between miRNA expression levels and the incidence risk of cALL. The receiver operating characteristic curve (ROC) and reclassification analysis were conducted to assess the feasibility of miRNAs serving as biomarkers for cALL. Results: A total of 204 differentially expressed miRNA were screened out and let-7f-5p, miR-5100, miR-25-3p and miR-3654 were selected for validation identified according to the inclusion criteria. The expression levels of let-7f-5p, miR-5100 and miR-25-3p in the cALL patients were significantly lower than those of the controls (P<0.01). After adjusting for confounding factors, 3 miRNAs remained significantly associated with the risk of cALL (OR and 95%CI were 0.84 (0.76-0.92), 0.81 (0.73-0.90) and 0.81 (0.74-0.89), respectively. Results from both the ROC analysis and reclassification analysis showed that introduction of one or more miRNA to traditional risk factors improved the area under the curve (P<0.05) and provided additional values to diagnosis (P<0.01). Conclusion: The expression levels of let-7f-5p, miR-5100 and miR-25-3p were significantly associated with the incidence rate of cALL, and these miRNAs might serve as promising biomarkers for cALL.

P5261The influence of acute leukemia chemotherapy and risk factors on the systolic function and arterial remodeling

P5261The influence of acute leukemia chemotherapy and risk factors on the systolic function and arterial remodeling

Correlation of patient prognosis with PU.1 and JDP2 to provide potential novel prognostic/diagnostic markers in MDS.

e18558 Background: PU.1 is a key transcription factor in haematopoiesis that plays important roles in various haematological malignancies. Previously, significant down-regulation of PU.1 has been reported in high risk myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) patients. Methods: To clarify PU.1 molecular function we investigated the gene expression of PU.1 and JDP2 (c-Jun dimerization protein-2), a member of the activating protein-1 family located downstream of PU.1, in bone marrow from 12 MDS patients stratified according to IPSS-R score (6-low, 3-intermediate, 3-high risk), 1 AML patient and 10 normal controls. Samples were enriched for the mononuclear fraction by Ficoll separation. Total RNA was extracted and analysed by Real Time PCR for PU.1 and JDP2 expression relative to the housekeeping gene GAPDHusing the 2-ΔΔCT method. Results: We revealed both PU.1 and JDP2 are down regulated in MDS. In addition, our data suggests that PU.1 and JDP2 expression inversely correlates with disease, with expression of these genes consistently reducing according to IPSS-R groups. Furthermore, a positive correlation of PU.1 and JDP2expression &lt; R = O.9333, s = 0.0004 &gt; , provides additional evidence that suppression of JDP2 by PU.1 could contribute to the pathogenesis of AML. Notably, PU.1 and JDP2 do not correlate to the same extent in normal HSCs, indicating that cofactors are required for PU.1 to exert its JDP2-regulating function and that such cofactors are not present under normal conditions. To confirm that JDP2 suppression is a direct result of reduced PU.1 we performed PU.1-knockdown in K562 cells stably expressing PU.1 short interfering RNAs versus control cells. These analyses reveal only a partial reduction in JDP2 expression when analysed by RT-PCR and Western blot, suggesting a more complex regulatory mechanism. Additionally, both PU.1 and JDP2 expression was recovered by treatment with azacitidine, which is routinely used to treat MDS, suggesting an involvement in treatment response. Conclusions: PU.1 and JDP2 expression correlates with patients prognosis highlighting a potential role as new diagnostic and prognostic markers in MDS.