Leukaemia is the most common cancer of childhood. The body produces lymphocytes to protect the body from infection, in leukaemia these cells do not mature properly and become too numerous in the blood and bone marrow. Leukaemias may be acute or chronic. The most common type is acute lymphoblastic leukaemia (ALL). There are a number of other less common acute types which may be grouped together as acute non-lymphoblastic leukaemia (ANLL), this includes acute myeloid leukaemia (AML).
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Targeting cancer genes to treat childhood leukaemia
Leukaemia & Lymphoma Research Dr Owen Williams talks about developing new drugs to treat childhood leukaemia. Dr Williams is from the UCL Institute of Child Health and Great Ormond Street Hospital for children NHS Trust.
The NCLF is a non-profit organization providing services, support, and referrals for leukemia patients and their families.The site provides details of their telephone help line, and information on various topics related to childhood leukemia.
PubMed Central search for free-access publications about Childhood Leukaemia MeSH term: Leukemia US National Library of Medicine PubMed has over 22 million citations for biomedical literature from MEDLINE, life science journals, and online books. Constantly updated.
SEER, National Cancer Institute Part of a SEER report on statistical trends and risk factors associated with childhood cancers. From: Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program 1975-1995. (PDF)
This list of publications is regularly updated (Source: PubMed).
Flower A, Cairo MS The evolution of allogeneic stem cell transplant for children and adolescents with acute myeloid leukemia. Clin Adv Hematol Oncol. 2017; 15(1):52-62 [PubMed] Related Publications
Survival rates in subsets of pediatric patients who have acute myeloid leukemia (AML) with favorable risk features are now greater than 90%. However, outcomes for patients with high-risk (HR) features remain unacceptably poor. As novel technologies for the identification of HR biomarkers and the detection of residual disease are developed, risk stratification and the application of allogeneic hematopoietic stem cell transplant (HSCT) are evolving. HSCT has been shown to benefit subpopulations of pediatric patients with AML, including those with HR cytogenetic translocations, genetic mutations, and/or residual disease after induction. Targeted therapies have shown promise for improving outcomes, and their integration into standard therapy and HSCT regimens is a critical area of interest. Also, expansion of the donor pool has led to the successful use of alternative donor sources for those patients without a matched sibling. However, transplant-related morbidity and mortality and late effects are major limiting factors. Reduced-intensity conditioning regimens have resulted in outcomes equivalent to those achieved with myeloablative regimens among patients in complete remission. The limitation of transplant-related morbidity and mortality through reduced-intensity conditioning and supportive care, and improved survival through optimal alloreactivity in combination with targeted therapy, are steps toward advancing outcomes for pediatric patients who have AML with HR features.
Lim JW, Yeap FS, Chan YH, et al. Second Malignant Neoplasms in Childhood Cancer Survivors Treated in a Tertiary Paediatric Oncology Centre. Ann Acad Med Singapore. 2017; 46(1):11-19 [PubMed] Related Publications
Introduction: One of the most feared complications of childhood cancer treatment is second malignant neoplasms (SMNs). This study evaluates the incidence, risk factors and outcomes of SMNs in a tertiary paediatric oncology centre in Singapore. Materials and Methods: A retrospective review was conducted on patients diagnosed with childhood cancer under age 21 and treated at the National University Hospital, Singapore, from January 1990 to 15 April 2012. Case records of patients with SMNs were reviewed. Results: We identified 1124 cases of childhood cancers with a median follow-up of 3.49 (0 to 24.06) years. The most common primary malignancies were leukaemia (47.1%), central nervous system tumours (11.7%) and lymphoma (9.8%). Fifteen cases developed SMNs, most commonly acute myeloid leukaemia/myelodysplastic syndrome (n = 7). Median interval between the first and second malignancy was 3.41 (0.24 to 18.30) years. Overall 20-year cumulative incidence of SMNs was 5.3% (95% CI, 0.2% to 10.4%). The 15-year cumulative incidence of SMNs following acute lymphoblastic leukaemia was 4.4% (95% CI, 0% to 8.9%), significantly lower than the risk after osteosarcoma of 14.2% (95% CI, 0.7% to 27.7%) within 5 years (P <0.0005). Overall 5-year survival for SMNs was lower than that of primary malignancies. Conclusion: This study identified factors explaining the epidemiology of SMNs described, and found topoisomerase II inhibitor use to be a likely risk factor in our cohort. Modifications have already been made to our existing therapeutic protocols in osteosarcoma treatment. We also recognised the importance of other risk management strategies, including regular long-term surveillance and early intervention for detected SMNs, to improve outcomes of high risk patients.
Eskandari-Nasab E, Hashemi M, Hasani SS, et al. Evaluation of functional RAGE gene polymorphisms in childhood acute lymphoblastic leukemia-A case-control study from Iran. Nucleosides Nucleotides Nucleic Acids. 2017; 36(3):170-180 [PubMed] Related Publications
We examined the possible relationship between three RAGE polymorphisms, -429C/T, -374 T/A, and 63-bp deletion, and susceptibility to childhood acute lymphoblastic leukemia (ALL) in an Iranian population. This study included 75 ALL patients and 115 healthy subjects. Genotyping was performed using HEXA-ARMS-polymerase chain reaction. We found no significant association among RAGE gene polymorphisms and the risk for ALL at genotype, allelic and haplotype levels (P > 0.05). The hemoglobin levels were higher in patients with RAGE -374 TT than in the TA carriers (P = 0.019). Our results demonstrated that the RAGE gene variations were not associated with risk of pediatrics ALL.
Serravalle S, Bertuccio SN, Astolfi A, et al. Synergistic Cytotoxic Effect of L-Asparaginase Combined with Decitabine as a Demethylating Agent in Pediatric T-ALL, with Specific Epigenetic Signature. Biomed Res Int. 2016; 2016:1985750 [PubMed] Free Access to Full ArticleRelated Publications
T-Acute Lymphoblastic Leukemia (T-ALL) remains a subgroup of pediatric ALL, with a lower response to standard chemotherapy. Some recent studies established the fundamental role of epigenetic aberrations such as DNA hypermethylation, to influence patients' outcome and response to chemotherapy. Moreover, L-asparaginase is an important chemotherapeutic agent for treatment of ALL and resistance to this drug has been linked to ASNS expression, which can be silenced through methylation. Therefore, we tested whether the sensitivity of T-ALL cell lines towards L-asparaginase is correlated to the epigenetic status of ASNS gene and whether the sensitivity can be modified by concurrent demethylating treatment. Hence we treated different T-ALL cell lines with L-asparaginase and correlated different responses to the treatment with ASNS expression. Then we demonstrated that the ASNS expression was dependent on the methylation status of the promoter. Finally we showed that, despite the demethylating effect on the ASNS gene expression, the combined treatment with the demethylating agent Decitabine could synergistically improve the L-asparaginase sensitivity in those T-ALL cell lines characterized by hypermethylation of the ASNS gene. In conclusion, this preclinical study identified an unexpected synergistic activity of L-asparaginase and Decitabine in the subgroup of T-ALL with low ASNS expression due to hypermethylation of the ASNS promoter, while it did not restore sensitivity in the resistant cell lines characterized by higher ASNS expression.
Leukemia is the most common pediatric cancer, affecting 3800 children per year in the United States. Its annual incidence has increased over the last decades, especially among Latinos. Although most children diagnosed with leukemia are now cured, many suffer long-term complications, and primary prevention efforts are urgently needed. The early onset of leukemia-usually before 5 years of age-and the presence at birth of "pre-leukemic" genetic signatures indicate that pre- and postnatal events are critical to the development of the disease. In contrast to most pediatric cancers, there is a growing body of literature-in the United States and internationally-that has implicated several environmental, infectious, and dietary risk factors in the etiology of childhood leukemia, mainly for acute lymphoblastic leukemia, the most common subtype. For example, exposures to pesticides, tobacco smoke, solvents, and traffic emissions have consistently demonstrated positive associations with the risk of developing childhood leukemia. In contrast, intake of vitamins and folate supplementation during the preconception period or pregnancy, breastfeeding, and exposure to routine childhood infections have been shown to reduce the risk of childhood leukemia. Some children may be especially vulnerable to these risk factors, as demonstrated by a disproportionate burden of childhood leukemia in the Latino population of California. The evidence supporting the associations between childhood leukemia and its risk factors-including pooled analyses from around the world and systematic reviews-is strong; however, the dissemination of this knowledge to clinicians has been limited. To protect children's health, it is prudent to initiate programs designed to alter exposure to well-established leukemia risk factors rather than to suspend judgment until no uncertainty remains. Primary prevention programs for childhood leukemia would also result in the significant co-benefits of reductions in other adverse health outcomes that are common in children, such as detriments to neurocognitive development.
Delvecchio M, Muggeo P, Monteduro M, et al. Non-alcoholic fatty liver disease is associated with early left ventricular dysfunction in childhood acute lymphoblastic leukaemia survivors. Eur J Endocrinol. 2017; 176(2):111-121 [PubMed] Related Publications
BACKGROUND: Childhood acute lymphoblastic leukaemia (ALL) survivors have an increased risk of metabolic and cardiovascular disease. We aimed to assess the presence of non-alcoholic fatty liver disease (NAFLD) in childhood ALL and if it is associated with early cardiovascular dysfunction. METHODS: In total, 53 childhood ALL survivors and 34 controls underwent auxological evaluation, biochemical assay, liver, heart and vascular ultrasound study. RESULTS: NAFLD was more frequent in ALL patients than in controls (39.6% vs 11.7%, P < 0.01). Patients with NAFLD were more obese and insulin resistant than patients without NAFLD. Flow-mediated dilatation and interventricular septum were lower in the ALL group than those in the control group (P < 0.001 for both). The patients with NAFLD showed lower left ventricular ejection fraction than those without NAFLD (P = 0.011). In ALL survivors, BMI-SDS and subcutaneous fat were the strongest predictors of NAFLD, whereas preperitoneal adipose tissue and C-reactive protein were the strongest predictors of left ventricular ejection fraction. CONCLUSIONS: Childhood ALL survivors had higher prevalence of NAFLD than healthy controls, which is associated with early left ventricular impairment. In the case of fatty liver, a comprehensive heart evaluation is mandatory. We strongly recommend to prevent visceral adiposity in ALL survivors, to search for metabolic syndrome or its components and to reinforce the need of intervention on diet and lifestyle during the follow-up of these patients.
Childhood acute lymphoblastic leukemia (ALL) occurs more frequently in males. Reasons behind sex differences in childhood ALL risk are unknown. In the present genome-wide association study (GWAS), we explored the genetic basis of sex differences by comparing genotype frequencies between male and female cases in a case-only study to assess effect-modification by sex.The case-only design included 236 incident cases of childhood ALL consecutively recruited at the Texas Children's Cancer Center in Houston, Texas from 2007 to 2012. All cases were non-Hispanic whites, aged 1 to 10 years, and diagnosed with confirmed B-cell precursor ALL. Genotyping was performed using the Illumina HumanCoreExome BeadChip on the Illumina Infinium platform. Besides the top 100 statistically most significant results, results were also analyzed by the top 100 highest effect size with a nominal statistical significance (P <0.05).The statistically most significant sex-specific association (P = 4 × 10) was with the single nucleotide polymorphism (SNP) rs4813720 (RASSF2), an expression quantitative trait locus (eQTL) for RASSF2 in peripheral blood. rs4813720 is also a strong methylation QTL (meQTL) for a CpG site (cg22485289) within RASSF2 in pregnancy, at birth, childhood, and adolescence. cg22485289 is one of the hypomethylated CpG sites in ALL compared with pre-B cells. Two missense SNPs, rs12722042 and 12722039, in the HLA-DQA1 gene yielded the highest effect sizes (odds ratio [OR] ∼ 14; P <0.01) for sex-specific results. The HLA-DQA1 SNPs belong to DQA1*01 and confirmed the previously reported male-specific association with DQA1*01. This finding supports the proposed infection-related etiology in childhood ALL risk for males. Further analyses revealed that most SNPs (either direct effect or through linkage disequilibrium) were within active enhancers or active promoter regions and had regulatory effects on gene expression levels.Cumulative data suggested that RASSF2 rs4813720, which correlates with increased RASSF2 expression, may counteract the suppressor effect of estrogen-regulated miR-17-92 on RASSF2 resulting in protection in males. Given the amount of sex hormone-related mechanisms suggested by our findings, future studies should examine prenatal or early postnatal programming by sex hormones when hormone levels show a large variation.
Avcu G, Karapinar DY, Akinci AB, et al. Utility of the serum galactomannan assay for the diagnosis of invasive aspergillosis in children with acute lymphoblastic leukemia. Int J Infect Dis. 2017; 54:8-12 [PubMed] Related Publications
OBJECTIVES: Invasive aspergillosis (IA) is an important cause of mortality and morbidity in children with hematological malignancies. The monitoring of serum galactomannan (GM) antigen is considered useful in the diagnosis of IA . The aim of this study was to determine the utility of serum GM monitoring in the early diagnosis of IA and the role of positive antigenemia in the management of children with acute lymphoblastic leukemia (ALL). METHODS: The cases of 141 children who were being treated for ALL in the Division of Pediatric Hematology of the Medical School of Ege University between January 2006 and February 2015 were reviewed retrospectively. Cases of proven and probable IA were defined according to the European Organization for the Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria. RESULTS: The incidence of proven and probable IA was 3.5% (5/141). The incidence of positive GM antigenemia among 3264 serum samples was 5.5% (n=179). Of the cases detected, 21.7% were true-positive, 52.1% were false-positive, and the remaining 26.1% were classified as 'undetermined.' An increase in the incidence of true-positive tests and induction of antifungal therapy was determined through multiple consecutive positive tests. CONCLUSIONS: GM may be detected in the serum before the clinical signs of IA appear, but its sensitivity and specificity are variable. False-positivity is a significant disadvantage, and consecutive positive GM must be taken into account in the case of clinical and imaging findings that are relevant to IA.
Al-Ghobashy MA, Hassan SA, Abdelaziz DH, et al. Development and validation of LC-MS/MS assay for the simultaneous determination of methotrexate, 6-mercaptopurine and its active metabolite 6-thioguanine in plasma of children with acute lymphoblastic leukemia: Correlation with genetic polymorphism. J Chromatogr B Analyt Technol Biomed Life Sci. 2016; 1038:88-94 [PubMed] Related Publications
Individualized therapy is a recent approach aiming to specify dosage regimen for each patient according to its genetic state. Cancer chemotherapy requires continuous monitoring of the plasma concentration levels of active forms of cytotoxic drugs and subsequent dose adjustment. In order to attain optimum therapeutic efficacy, correlation to pharmacogenetics data is crucial. In this study, a specific, accurate and sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) has been developed for determination of methotrexate (MTX), 6-mercaptopurine (MP) and its metabolite 6-thioguanine nucleotide (TG) in human plasma. Based on the basic character of the studied compounds, solid phase extraction using a strong cation exchanger was found the optimum approach to achieve good extraction recovery. Chromatographic separation was carried out using RP-HPLC and isocratic elution by acetonitrile: 0.1% aqueous formic acid (85:15v/v) with a flow rate of 0.8mL/min at 40°C. The detection was performed by tandem mass spectrometry in MRM mode via electrospray ionization source in positive ionization mode. Analysis was carried out within 1.0min over a concentration range of 6.25-200.00ng/mL for the studied analytes. Validation was carried out according to FDA guidelines for bioanalytical method validation and satisfactory results were obtained. The applicability of the assay for the monitoring of the MTX, MP and TG and subsequent application to personalized therapy was demonstrated in a clinical study on children with acute lymphoblastic leukemia (ALL). Results confirmed the need for implementation of reliable analysis tools for therapeutic dose adjustment.
Hale V, Hale GA, Brown PA, Amankwah EK A Review of DNA Methylation and microRNA Expression in Recurrent Pediatric Acute Leukemia. Oncology. 2017; 92(2):61-67 [PubMed] Related Publications
Acute leukemia is the most common childhood cancer diagnosis and leading cause of cancer-related death among children and adolescents. Despite substantial improvements in the survival rate of childhood acute leukemia, approximately 20-40% of the patients who undergo treatment develop relapse, with a dismal one third of these patients surviving in the long term. Epigenetics plays an important role in the progression of cancer, and existing evidence suggests a role in childhood acute leukemia relapse. A better understanding of the epigenetic mechanisms in recurrent acute leukemia could potentially lead to novel therapeutic regimens to prevent or treat disease recurrences. In this review, we summarize existing evidence on two of the most studied epigenetic mechanisms, DNA methylation and microRNA expression, in recurrent pediatric acute leukemia.
Portich JP, Gil MS, Dos Santos RP, et al. Low brain-derived neurotrophic factor levels are associated with active disease and poor prognosis in childhood acute leukemia. Cancer Biomark. 2016; 17(3):347-352 [PubMed] Related Publications
BACKGROUND: Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related receptor kinase B (TrkB) are involved in the maturation of B lymphocytes in the bone marrow (BM), promote cell differentiation in B-cell malignancies, and are associated with poor prognosis in adults with acute leukemia (AL). However, the role of BDNF in pediatric AL remains poorly understood. OBJECTIVE: We carried out a cohort observational study to evaluate BDNF levels in BM or peripheral blood (PB) samples from children with AL. METHODS: BM or PB samples were collected from 57 children and adolescents with acute lymphoid leukemia (ALL), 14 children and adolescents with acute myeloid leukemia (AML), and 44 healthy individuals (HI) of the same age range. RESULTS: BDNF levels at diagnosis in AL patients were significantly lower when compared to HI. Samples from patients in complete remission from disease had higher levels of BDNF compared to those obtained from patients with malignant cells. Moreover, BDNF levels at diagnosis in patients who died were significantly lower compared to those found in survivors. CONCLUSIONS: These findings provide the first evidence for a possible role of BDNF as a marker of active disease and poor prognosis in pediatric AL.
Pei JS, Hsu PC, Chou AK, et al. Matrix Metalloproteinase-1 Genotype Contributes to the Risk of Non-solid Tumor in Childhood Leukemia. Anticancer Res. 2016; 36(10):5127-5132 [PubMed] Related Publications
AIM: Up-regulation of metalloproteinase (MMPs) proteins have been shown in various types of solid cancers and the genotype of MMP1 has been associated with the risk of solid cancers. However, the contribution of MMP1 genotype to leukemia has never been investigated to our knowledge. Therefore, in this study we aimed to evaluate the contribution of the genotypic variants in the promoter region of MMP1 to childhood acute lymphoblastic leukemia (ALL) risk in Taiwan. MATERIALS AND METHODS: In this case-control study, 266 patients with childhood ALL and 266 non-cancer controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism methodology. RESULTS: The distribution of 2G/2G, 1G/2G and 1G/1G for MMP1 promoter rs1799750 genotype was 49.2%, 39.5% and 11.3% in the childhood ALL group and 36.8%, 43.6% and 19.5% in the non-cancer control group, respectively (p for trend=0.0046), significantly differentially distributed between childhood ALL and control groups. The carrier comparisons in dominant and recessive models also support the findings that 1G appears to be the protective allele in childhood ALL. In genotype and gender interaction analysis, it was found that boys carrying the MMP1 rs1799750 1G/2G or 1G/1G genotypes had lower odds ratios(ORs) of 0.68 and 0.43 [95% confidence intervals (CI)=0.47-0.98 and 0.26-0.73, p=0.0395 and 0.0013, respectively] for childhood ALL than those carrying the 2G/2G genotype. Analysis of genotype inaction with age of onset age showed those aged less than 3.5 years at onset carrying the 1G/2G or 1G/1G genotypes had lower ORs (0.0183 and 0.0004, respectively) for childhood ALL, but there was no such difference for those having an age at onset of 3.5 years or more. CONCLUSION: Our results indicate that the MMP1 rs1799750 1G allele is a protective biomarker for childhood ALL.
Takita J Genetic and epigenetic aberrations of pediatric leukemia and clinical applications. Rinsho Ketsueki. 2016; 57(10):2294-2300 [PubMed] Related Publications
Pediatric acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. Although fusion genes generated by chromosomal rearrangements are the most frequent genetic alterations in pediatric ALL, fusions are insufficient for the development of this disease, and thus, cannot serve as therapeutic targets for ALL. Recently, integrated genetic analysis using next generation sequencing technology has revealed the genetic landscapes of pediatric ALL. These studies disclosed that in addition to fusion genes, aberrations of cell proliferation pathways and epigenetic regulations are also involved in the pathogenesis of pediatric ALL. On the other hand, more recently, abnormalities of supper enhancer regions of TAL1 have been detected as a novel oncogenic mechanism of pediatric T cell ALL. Furthermore, germline mutations of ARID5B, PAX5, and GATA3 have been found to be involved in the genetic risk of developing ALL. Therefore, currently, the molecular mechanisms of pediatric ALL have been fully disclosed.
Rutkauskaitė V, Ragelienė L, Matuzevičienė R, et al. Reduction in Proportion of Senescent CD8+ T Lymphocytes During Chemotherapy of Children with Acute Lymphoblastic Leukemia. Anticancer Res. 2016; 36(11):6195-6199 [PubMed] Related Publications
AIM: To evaluate quantitative changes in B, NK and T lymphocyte subsets in peripheral blood of children with acute lymphoblastic leukemia (ALL) undergoing chemotherapy. PATIENTS AND METHODS: Children with ALL were treated according to NOPHO ALL 2008 protocol. Levels of B lymphocytes (CD19(+)), NK cells (CD3(-)CD56(+)) and subsets of T lymphocytes (CD3(+)CD4(+), CD4(+)CD25(+)Foxp3(+), CD3(+)CD8(+), CD3(+)CD8(+)CD57(+), CD3(+)CD8(+)CD57(-)) in peripheral blood were analyzed by flow cytometry prior and during treatment with cytotoxic drugs. RESULTS: Immunological analyses were performed in 25 children with ALL. Levels of B and NK lymphocytes decreased continuously during chemotherapy. In contrast, levels of most T lymphocyte subsets decreased only transiently and returned to pretreatment levels by days 78 to 85. The only T lymphocyte subset that did not return to the pretreatment level contained senescent CD3(+)CD8(+)CD57(+) lymphocytes. CONCLUSION: Immunomodulating action of chemotherapy in children with ALL results in reduction of proportion of senescent CD8(+) T lymphocytes.
BACKGROUND: Although adenovirus (ADV) infection usually causes self-limiting respiratory disorders in immune competent children; severe and systemic ADV infection in children undergoing chemotherapy for leukemia has been continuously reported. Nevertheless, there has been no consensus on risk factors and treatment strategies for severe ADV infection in children undergoing chemotherapy. CASE SUMMARY: We report a case of a 15-year-old boy with a fatal systemic ADV infection. He had received reinduction chemotherapy for relapsed acute lymphoblastic leukemia under continuing antifungal therapy for previously diagnosed fungal pneumonia. He complained of fever and right shoulder pain 4 days after completing the reinduction chemotherapy. In spite of appropriate antibiotic and antifungal therapy, pneumonia was aggravated and gross hematuria was accompanied. A multiplex polymerase chain reaction test for respiratory viruses was positive for ADV in a blood sample, and a urine culture was positive for ADV. He received oral ribavirin, intravenous immunoglobulin, and intravenous cidofovir therapy; however, he eventually died. Relapsed leukemia, concurrent fungal pneumonia, and delayed cidofovir administration were considered the cause of the grave outcome in this patient. CONCLUSION: ADV may cause severe infections not only in allogeneic hematopoietic cell transplant recipients, but also in patients undergoing chemotherapy for acute leukemia. The risk factors for severe ADV infection in patients undergoing chemotherapy should be determined in the future studies, and early antiviral therapy should be administered to immune compromised patients with systemic ADV infection.
Ramírez-Pacheco A, Moreno-Guerrero S, Alamillo I, et al. Mexican Childhood Acute Lymphoblastic Leukemia: A Pilot Study of the MDR1 and MTHFR Gene Polymorphisms and Their Associations with Clinical Outcomes. Genet Test Mol Biomarkers. 2016; 20(10):597-602 [PubMed] Related Publications
BACKGROUND: Genetic polymorphisms in patients with acute lymphoblastic leukemia (ALL) may influence the toxicity of chemotherapeutic agents. Due to the importance of the transport P-glycoprotein and methylenetetrahydrofolate reductase in the metabolism of chemotherapeutic agents, we analyzed the MDR1 rs1045642 and MTHFR rs1801133 polymorphisms and their associations with clinical outcomes in Mexican childhood ALL patients. METHODS: A total of 109 patients participated in this study. The clinical evaluation consisted of a physical examination and a laboratory test. Genotyping of MDR1 rs1045642 (3435 C>T) and MTHFR rs1801133 (677 C>T) was performed by polymerase chain reaction/restriction fragment length polymorphism. Statistical analyses were performed using SPSS 14.0. The odds ratios and 95% confidence intervals (CI) were estimated by logistic regression. RESULTS: Individuals who were CC homozygotes at MDR1 rs1045642 had lower risk of having methotrexate plasma concentrations >1 μM and leukopenia grade I (odds ratio [OR] = 0.30; 95% CI = 0.13-0.72 and OR = 0.32; 95% CI = 0.14-0.72, respectively). Patients who were CC homozygotes at MTHFR rs1801133 had a higher risk of developing mucositis (OR = 3.61; 95% CI = 1.42-9.14). CONCLUSION: MDR1 rs1045642 and MTHFR rs1801133 should be considered as diagnostic candidates for the identification of pediatric patients with a high risk of suffering adverse events during ALL treatment.
Wu X, Feng X, Zhao X, et al. Role of Beclin-1-Mediated Autophagy in the Survival of Pediatric Leukemia Cells. Cell Physiol Biochem. 2016; 39(5):1827-1836 [PubMed] Related Publications
BACKGROUND/AIMS: Acute and chronic leukemia are severe malignant cancers worldwide, and can occur in pediatric patients. Since bone marrow cell transplantation is seriously limited by the availability of the immune-paired donor sources, the therapy for pediatric leukemia (PL) remains challenging. Autophagy is essential for the regulation of cell survival in the harsh environment. However, the role of autophagy in the survival of PL cells under the oxidative stress, e.g. chemotherapy, remain ill-defined. In the current study, we addressed these questions. METHODS: We analyzed the effects of oxidative stress on the cell viability of PL cells in vitro, using a CCK-8 assay. We analyzed the effects of oxidative stress on the apoptosis and autophagy of PL cells. We analyzed the levels of Beclin-1 and microRNA-93 (miR-93) in PL cells. Prediction of binding between miR-93 and 3'-UTR of Beclin-1 mRNA was performed by a bioinformatics algorithm and confirmed by a dual luciferase reporter assay. The relationship between levels of miR-93 and patients' survival was analyzed in PL patients. RESULTS: We found that oxidative stress dose-dependently increased autophagy in PL cells. While low-level oxidative stress did not increase apoptosis, high-level oxidative stress increased apoptosis, seemingly from failure of autophagy-mediated cell survival. High-level oxidative stress appeared to suppress the protein levels of an autophagy protein Beclin-1 in PL cells, possibly through induction of miR-93, which inhibited the translation of Beclin-1 mRNA via 3'-UTR binding. CONCLUSION: Beclin-1-mediated autophagy plays a key role in the survival of PL cells against oxidative stress. Induction of miR-93 may increase the sensitivity of PL cells to oxidative stress during chemotherapy to improve therapeutic outcome.
Wang X, Zuo D, Yuan Y, et al. MicroRNA-183 promotes cell proliferation via regulating programmed cell death 6 in pediatric acute myeloid leukemia. J Cancer Res Clin Oncol. 2017; 143(1):169-180 [PubMed] Related Publications
PURPOSE: The aim of this study was to investigate roles of microRNA (miR)-183 in pediatric acute myeloid leukemia (AML). METHODS: miR-183 expression in bone marrow and patients' sera of childhood AML was detected by real-time quantitative PCR. Functions of miR-183 in malignant phenotypes of two leukemia cell lines were then evaluated. Additionally, putative targets of miR-183 were predicted using three miRNA target prediction algorithms and validated by luciferase reporter assay. Clinical relevance of miR-183 and its target gene were further determined. RESULTS: miR-183 expression in bone marrow and patients' sera of childhood AML was both significantly higher than those in the corresponding normal controls (both P < 0.001). Enforced expression of miR-183 dramatically enhanced cell proliferation and G1/S transition, but inhibited cell apoptosis of leukemia cells. Bioinformatics prediction and luciferase reporter assay identified programmed cell death 6 (PDCD6) as a direct target gene of miR-183. Moreover, high serum miR-183 combined with low serum PDCD6 mRNA was significantly associated with French-American-British classification subtype M7 (P = 0.01) and unfavorable karyotypes (P = 0.006). Further multivariate analysis identified the combination of serum miR-183 and PDCD6 levels as an independent prognostic factor for both relapse-free and overall survivals. Functionally, re-introduction of PDCD6 markedly reversed the effects of miR-183 in cell cycle, proliferation and apoptosis of two leukemia cell lines. CONCLUSION: Combined serum miR-183 and PDCD6 mRNA may serve as a novel prognostic biomarker for pediatric AML. Interestingly, miR-183 may function as an oncogene and may enhance cell proliferation by targeting PDCD6, implying a potential therapeutic target for this malignancy.
Baranger L, Cuccuini W, Lefebvre C, et al. Cytogenetics in the management of children and adult acute lymphoblastic leukemia (ALL): an update by the Groupe francophone de cytogénétique hématologique (GFCH). Ann Biol Clin (Paris). 2016; 74(5):547-560 [PubMed] Related Publications
Cytogenetic analyses (karyotype and, if necessary, appropriate complementary FISH analyses) are mandatory at diagnosis in acute lymphoblastic leukemia (ALL) as their results are taken into account in therapeutic protocols due to their diagnostic and prognostic values. In some cases, karyotype can be completed by other techniques (RT-PCR, RQ-PCR, DNA content, SNP-array, MLPA…) that can be equally or more informative than FISH. Here, we have tempted to establish guidelines concerning karyotype and FISH analyses according to the most recent data of the litterature which is reviewed here, completing the 2008 WHO classification with the recent new cytogenomic entities such as Ph-like ALL and indicating possible therapeutic implications.
Bhandari P, Ahmad F, Mandava S, Das BR Association of Genetic Variants in ARID5B, IKZF1 and CEBPE with Risk of Childhood de novo B-Lineage Acute Lymphoblastic Leukemia in India. Asian Pac J Cancer Prev. 2016; 17(8):3989-95 [PubMed] Related Publications
BACKGROUND: Childhood acute lymphoblastic leukemia (ALL) is a heterogeneous genetic disease and its etiology remains poorly understood. Recent genome wide association and replication studies have highlighted specic polymorphisms contributing to childhood ALL predispositions mostly in European populations. It is unclear if these observations generalize to other populations with a lower incidence of ALL. The current case-control study evaluated variants in ARID5B (rs7089424, rs10821936), IKZF1 (rs4132601) and CEBPE (rs2239633) genes, which appear most significantly associated with risk of developing childhood B-lineage ALL. MATERIALS AND METHODS: Using TaqMan assays, genotyping was conducted for 162 de novo B-lineage ALL cases and 150 unrelated healthy controls in India. Appropriate statistical methods were applied. RESULTS: Genotypic and allelic frequencies differed significantly between cases and controls at IKZF1-rs4132601 (p=0.039, p=0.015) and ARID5B-rs10821936 (p=0.028, p=0.026). Both rs10821936 (p=0.019; OR 0.67; 95% CI=0.47-0.94) and rs4132601 (p=0.018; OR 0.67; 95%CI 0.48-0.94) were associated with reduced disease risk. Moreover, gender- analysis revealed male-specific risk associations for rs10821936 (p=0.041 CT+CC) and rs4132601 (p=0.005 G allele). Further, ARID5B-rs7089424 and CEBPE-rs2239633 showed a trend towards decreased disease risk but without significance (p=0.073; p=0.73). CONCLUSIONS: Our findings provide the rst evidence that SNPs ARID5B- rs10821936 and IKZF1-rs4132601 are associated with decreased B-lineage ALL susceptibility in Indian children. Understanding the effects of these variants in different ethnic groups is crucial as they may confer different risk of ALL within different populations.
Bahari G, Hashemi M, Naderi M, Taheri M TET2 Promoter DNA Methylation and Expression in Childhood Acute Lymphoblastic Leukemia. Asian Pac J Cancer Prev. 2016; 17(8):3959-62 [PubMed] Related Publications
The ten-eleven-translocation-2 (TET2) gene is a novel tumor suppressor gene involved in several hematological malignancies of myeloid and lymphoid origin. Besides loss-of-function mutations and deletions, hypermethylation of the CpG island at the TET2 promoter has been found in human cancers. The TET2 encoded protein regulates DNA methylation. The present study aimed to examine DNA promoter methylation of TET2 in 100 childhood acute lymphoblastic leukemia (ALL) cases and 120 healthy children in southeast Iran. In addition, mRNA expression levels were assessed in 30 new cases of ALL and 32 controls. Our findings indicated that promoter methylation of TET2 significantly increases the risk of ALL (OR=2.60, 95% CI=1.31-5.12, p=0.0060) in comparison with absent methylation. Furthermore, the TET2 gene was significantly downregulated in childhood ALL compared to healthy children (p=0.0235). The results revealed that hypermethylation and downregulation of TET2 gene may play a role in predisposition to childhood ALL. Further studies with larger sample sizes and different ethnicities are needed to confirm our findings.
Goto Y, Nishimura R, Nohara A, et al. Minimal contribution of severe hypertriglyceridemia in L-asparaginase-associated pancreatitis developed in a child with acute lymphocytic leukemia. Rinsho Ketsueki. 2016; 57(8):994-8 [PubMed] Related Publications
A 10-year-old girl developed L-asparaginase (ASP)-associated pancreatitis during chemotherapy for acute lymphocytic leukemia. Her symptoms showed alleviation with continuous regional arterial infusion of protease inhibitor and systemic somatostatin analog therapy. She had intermittent and marked hypertriglyceridemia, an initial trigger for pancreatitis, probably as a side effect of ASP and steroids. However, we considered the pancreatitis to have developed mainly because of factors other than hypertriglyceridemia as lipoprotein analysis confirmed chylomicron levels to be nearly undetectable. Extremely large chylomicrons contribute directly to the onset of pancreatitis by causing blockage of small vessels. Although it is necessary to examine patients for dyslipidemia developing as a side effect of ASP, therapeutic intervention for hypertriglyceridemia is not considered to prevent the onset of ASP-associated pancreatitis.
Huang QT, Gao YF, Zhong M, Yu YH Preterm Birth and Subsequent Risk of Acute Childhood Leukemia: a Meta-Analysis of Observational Studies. Cell Physiol Biochem. 2016; 39(3):1229-38 [PubMed] Related Publications
BACKGROUND: Preterm birth (PTB) has been recognized as a crucial long term risk factor for multiple non-communicable diseases. However, studies between the relationship of PTB and the risk of acute childhood leukemia have yielded inconclusive results. Therefore, we performed a meta-analysis to systematically review the current literature to investigate whether PTB is associated with increased risk of acute childhood leukemia. METHODS: Three electronic databases (PubMed, Web of Science, and EMBASE) were searched up to December 1st, 2015. Relevant studies reporting the association between PTB and subsequent risk of acute childhood leukemia were included for further evaluation. Statistical analysis was performed using Revmen 5.3 and Stata 10.0. RESULTS: A total of 12 studies for acute childhood leukemia, eight studies for acute lymphoblastic leukemia (ALL), and seven studies for acute myeloid leukemia (AML) were included in the current meta-analyses. We calculated pooled odds ratio (OR) and 95% confidence interval (CI) to evaluate the relationship between PTB and acute childhood leukemia as well as its two subtypes: ALL and AML. Our results suggested that PTB was significantly associated with increased risk of acute childhood leukemia (OR = 1.09, 95% CI = 1.02-1.17, P = 0.01) and AML (OR = 1.42, 95% CI = 1.21-1.67, P < 0.01). However, PTB was not significantly associated with an increased risk of ALL (OR = 1.04, 95% CI = 0.96-1.13, P = 0.29). CONCLUSION: Our data showed that PTB increased the risk of AML. Further studies are required to explore causality and dissect the biological mechanisms involved.
Yoshida K Genetic abnormalities associated with the relapse of childhood leukemia. Rinsho Ketsueki. 2016; 57(7):919-24 [PubMed] Related Publications
Acute leukemia, especially acute lymphoblastic leukemia, is the most common tumor in childhood. Survival in pediatric acute leukemia cases has improved significantly, but once a relapse occurs, the long-term survival rates decrease markedly. Recently, SNP array and next-generation sequencing have revealed the relapse mechanism of pediatric leukemia and genetic alterations which drive leukemia recurrence.
Takagi M, Urayama K Inherited genetic variants associated with childhood acute lymphoblastic leukemia risk. Rinsho Ketsueki. 2016; 57(7):891-9 [PubMed] Related Publications
Numerous efforts have been made to elucidate the roles of individual genetic background factors in the risk of childhood acute lymphoblastic leukemia. Most have taken the form of case-control studies focusing on specific candidate gene polymorphisms. Recently, a more rigorous and comprehensive approach referred to as a genome-wide association study (GWAS) has been widely utilized and has achieved success. Case-control studies evaluating candidate gene associations have shown cumulative evidence of a role for folate metabolism and xenobiotic metabolism/transport pathway genetic variants. In addition, single nucleotide polymorphism (SNP)s identified by GWAS appear to indicate a strong role for genes encoding transcription factors involved in cellular differentiation. Further studies are needed to clarify the accumulating evidence obtained from both candidate gene and genome-wide investigations.
Hagag AA, Elmashad GM, Abd El-Bar ES Prognostic value of Prominin-1 Expression in Egyptian children with Acute Lymphoblastic Leukemia: Two centers Egyptian study. J Cancer Res Ther. 2016 Apr-Jun; 12(2):627-33 [PubMed] Related Publications
OBJECTIVES: Acute lymphoblasstic leukemia (ALL) is the most common childhood malignancy. Prominin-1 is a cell-surface trans-membrane glycoprotein expressed on the stem cell surface and has potential role in diagnostic and prognostic work-up of several stem cell cancers. Aim of this Work: To assess the prognostic value of Prominin-1 expression in Egyptian children with ALL. SUBJECTS AND METHODS: This study was conducted on 80 Egyptian children with newly diagnosed ALL and 30 healthy children of matched age and sex as a control group. Patient history, and clinical and laboratory examination results were taken, including complete blood count, serum LDH, bone marrow aspiration with cytochemistry, immunophenotyping, Fluorescent In Situ Hybridization technique for detection of t(9;22) and Flow cytometery for estimation of Prominin-1 expression on blast cells. RESULTS: No statistically significant differences were observed between Prominin-1 positive and negative patients regarding age, sex and clinical presentation at diagnosis. No statistically significant differences between Prominin-1 positive and negative patients were observed regarding white blood cells and platelet counts, peripheral blood and bone marrow blast cells percentage while there were significantly higher hemoglobin and LDH levels in Prominin-1 positive patients. There were no significant differences between Prominin-1 positive and negative patients regarding immunophenotyping and t(9;22). There were statistically significant differences in disease outcome between Prominin-1 positive and negative expression with higher rate of relapse and death and lower rate of complete remission in patients with Prominin-1 positive expression (14 cases with Prominin-1 positive relapsed versus 2 cases with Prominin-1 negative, 12 cases with Prominin-1 positive died versus 2 cases with Prominin-1 negative and complete remission occurred in 20 cases with Prominin-1 positive versus 30 cases with Prominin-1 negative) (P =0.017). There was statistically significant difference in disease-free survival (P = 0.0072) and overall survival (P = 0.0424) between ALL patients with Prominin-1 positive and Prominin--1 negative expression. CONCLUSION: Prominin-1 is a helpful prognostic marker in patients with ALL; therefore, it should be routinely assessed at diagnosis in ALL patients for better prognostic assessment and should be taken in consideration in designing future therapeutic strategies based on patient-specific risk factors.
Sharma M, Sachdeva MU, Varma N, et al. Characterization of immunophenotypic aberrancies in adult and childhood acute lymphoblastic leukemia: A study from Northern India. J Cancer Res Ther. 2016 Apr-Jun; 12(2):620-6 [PubMed] Related Publications
BACKGROUND: Identification of aberrant antigen expression is important in characterizing neoplastic population among non.neoplastic bone marrow counterparts and further in the detection of minimal residual disease. (MRD). Flow cytometry (FCM) is an important tool in identifying aberrant phenotypes. Incidence of aberrant phenotypes varies considerably in independent studies and its association with prognostic factors is still debatable. AIM: To identify the prevalence of aberrant phenotypes on immunophenotyping in a large series of de novo acute lymphoblastic leukemia (ALL) and to evaluate any association with initial clinical and hematological features. MATERIALS AND METHODS: In the current study, 303 patients of de novo ALL were included from the Department of Hematology, PGIMER, Chandigarh during the time period (July 2010 to June 2012). The immunophenotype of all cases of ALL was studied using FCM. RESULTS: Aberrant myeloid antigen expression was seen in 42.5% cases. Most frequent aberrant myeloid antigen was CD13 (32.2% cases), followed by CD33 (27.2% cases) and CD117 (18.5% cases). The expression of CD117 was relatively frequent in comparison to earlier reports which describe its rare expression. Adult T- ALL showed higher expression of CD33 and CD117 than pediatric T-ALL (P = 0.032 and 0.043, respectively). Myeloid antigen expression in ALL was associated with lower WBC count (P < 0.05) and lower number of peripheral blasts (P < 0.05). Expression of CD34 was higher in My + ALL group (P < 0.05) than My- ALL group. CONCLUSION: In summary, CD117 is a relatively frequently expressed myeloid marker contrary to earlier reports which describes its rare expression. Pediatric and adult ALL cases with low blast count and CD34 positivity are more likely to express aberrant myeloid markers. Current study also supports that myeloid antigen expression in both adult and pediatric ALL is not associated with adverse presenting clinical and biological features.
Marjanovic I, Kostic J, Stanic B, et al. Parallel targeted next generation sequencing of childhood and adult acute myeloid leukemia patients reveals uniform genomic profile of the disease. Tumour Biol. 2016; 37(10):13391-13401 [PubMed] Related Publications
The age-specific differences in the genetic mechanisms of myeloid leukemogenesis have been observed and studied previously. However, NGS technology has provided a possibility to obtain a large amount of mutation data. We analyzed DNA samples from 20 childhood (cAML) and 20 adult AML (aAML) patients, using NGS targeted sequencing. The average coverage of high-quality sequences was 2981 × per amplicon. A total of 412 (207 cAML, 205 aAML) variants in the coding regions were detected; out of which, only 122 (62 cAML and 60 aAML) were potentially protein-changing. Our results confirmed that AML contains small number of genetic alterations (median 3 mutations/patient in both groups). The prevalence of the most frequent single gene AML associated mutations differed in cAML and aAML patient cohorts: IDH1 (0 % cAML, 5 % aAML), IDH2 (0 % cAML, 10 % aAML), NPM1 (10 % cAML, 35 % aAML). Additionally, potentially protein-changing variants were found in tyrosine kinase genes or genes encoding tyrosine kinase associated proteins (JAK3, ABL1, GNAQ, and EGFR) in cAML, while among aAML, the prevalence is directed towards variants in the methylation and histone modifying genes (IDH1, IDH2, and SMARCB1). Besides uniform genomic profile of AML, specific genetic characteristic was exclusively detected in cAML and aAML.
Marcos-Gragera R, Galceran J, Martos C, et al. Incidence and survival time trends for Spanish children and adolescents with leukaemia from 1983 to 2007. Clin Transl Oncol. 2017; 19(3):301-316 [PubMed] Related Publications
OBJECTIVE: We have analysed incidence and survival trends of children and adolescents with leukaemia registered in Spanish population-based cancer registries during the period 1983-2007. METHODS: Childhood and adolescent leukaemia cases were drawn from the 11 Spanish population-based cancer registries. For survival, registries with data for the period 1991-2005 and follow-up until 31-12-2010 were included. Overall incidence trends were evaluated using joinpoint analysis. Observed survival rates were estimated using Kaplan-Meier, and trends were tested using the log-rank test. RESULTS: Based on 2606 cases (2274 children and 332 adolescents), the overall age-adjusted incidence rate (ASRw) of leukaemia was 47.9 cases per million child-years in children and 23.8 in adolescents. The ASRw of leukaemia increased with an annual percentage change of 9.6 % (95 % CI: 2.2-17.6) until 1990 followed by a stabilisation of rates. In adolescents, incidence did not increase. Five-year survival increased from 66 % in 1991-1995 to 76 % in 2001-2005. By age, survival was dramatically lower in infants (0) and adolescents (15-19) than in the other age groups and no improvement was observed. In both children and adolescents, differences in 5-year survival rates among major subgroups of leukaemias were significant. CONCLUSIONS: The increasing incidence trends observed in childhood leukaemias during the study period were confined to the beginning of the period. Remarkable improvements in survival have been observed in Spanish children with leukaemias. However, this improvement was not observed in infants and adolescents.
Wu X, Feng X, Zhao X, et al. Prognostic significance of FLT3-ITD in pediatric acute myeloid leukemia: a meta-analysis of cohort studies. Mol Cell Biochem. 2016; 420(1-2):121-8 [PubMed] Related Publications
The purpose of the study was to assess the effect of the internal tandem duplication in FMS-like tyrosine kinase 3 (FLT3-ITD) on the outcome in pediatric acute myeloid leukemia (AML) patients. We identified eligible studies from several databases including PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) (from January 1995 to July 2015). Ten studies of 1661 pediatric patients with AML were included in exploring the relationship between the FLT3-ITD and overall survival (OS)/event free survival (EFS). Pediatric patients with AML with FLT3-ITD had worse OS [HR = 2.19 (1.60-3.01)]/EFS [HR = 1.70 (1.37-2.11)] than those patients without FLT3-ITD. Furthermore, FLT3-ITD had unfavorable effect on OS/EFS in the subgroups of NOS, uni/multivariate model, number of patients, the length of following-up, and patient source. The findings of this meta-analysis indicated that FLT3-ITD had negative impact on pediatric patients with AML.