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Cancer Genomics & Proteomics 2024The capacity for non-homologous end-joining (NHEJ) repair plays a pivotal role in maintaining genome stability and in carcinogenesis. However, there is little literature...
BACKGROUND/AIM
The capacity for non-homologous end-joining (NHEJ) repair plays a pivotal role in maintaining genome stability and in carcinogenesis. However, there is little literature on the involvement of NHEJ-related genes in childhood acute lymphocytic leukemia (ALL). Our study aimed to elucidate the impact of polymorphisms of X-ray repair cross-complementing group 4 (XRCC4) (rs6869366, rs2075685, rs2075686, rs28360071, rs3734091, rs28360317, rs1805377), XRCC5 (rs828907, rs11685387, rs9288518), XRCC6 (rs5751129, rs2267437, rs132770, rs132774), XRCC7 rs7003908, and DNA ligase IV (LIG4) rs1805388, on the odds of childhood ALL.
MATERIALS AND METHODS
Genotypes NHEJ-related genes of 266 cases and 266 controls were determined, and the genotype-phenotype correlation was investigated by examining mRNA transcript expression and the capacity for overall and precise NHEJ repair.
RESULTS
The variant genotypes of XRCC4 rs3734091, rs28360071, XRCC5 rs828907, and XRCC6 rs5751129 were significantly associated with increased odds of childhood ALL. Further analysis based on susceptibility genotypes showed no significant differences in mRNA transcript expression levels among childhood ALL cases with various putative high-risk genotypes, except XRCC6 rs5751129. Moreover, the overall NHEJ repair capacity was similar among carriers of different XRCC4, XRCC5, and XRCC6 genotypes. However, it is worth noting that individuals carrying the variant C allele at XRCC6 rs5751129 exhibited lower precise NHEJ repair capacity compared to those with the wild-type T allele.
CONCLUSION
Our study identified significant associations between XRCC4 rs3734091, rs28360071, XRCC5 rs828907, and XRCC6 rs5751129 genotypes and childhood ALL. Notably, lower transcriptional expression and reduced precise NHEJ repair capacity were observed in patients carrying the C allele of XRCC6 rs5751129. Further investigations are required to gain deeper insights into childhood ALL development.
Topics: Humans; Genotype; Alleles; Precursor Cell Lymphoblastic Leukemia-Lymphoma; DNA Repair; RNA, Messenger; Genetic Predisposition to Disease; Case-Control Studies; Polymorphism, Single Nucleotide
PubMed: 38423600
DOI: 10.21873/cgp.20436 -
Leukemia Sep 2016Children with Down syndrome (DS) are at a 20-fold increased risk for acute lymphoblastic leukemia (DS-ALL). Although the etiology of this higher risk of developing... (Review)
Review
Children with Down syndrome (DS) are at a 20-fold increased risk for acute lymphoblastic leukemia (DS-ALL). Although the etiology of this higher risk of developing leukemia remains largely unclear, the recent identification of CRLF2 (cytokine receptor like factor 2) and JAK2 mutations and study of the effect of trisomy of Hmgn1 and Dyrk1a (dual-specificity tyrosine phosphorylation-regulated kinase 1A) on B-cell development have shed significant new light on the disease process. Here we focus on the clinical features, biology and genetics of ALL in children with DS. We review the unique characteristics of DS-ALL on both the clinical and molecular levels and discuss the differences in treatments and outcomes in ALL in children with DS compared with those without DS. The identification of new biological insights is expected to pave the way for novel targeted therapies.
Topics: B-Lymphocytes; Child; Down Syndrome; Humans; Molecular Targeted Therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Treatment Outcome
PubMed: 27285583
DOI: 10.1038/leu.2016.164 -
Human Vaccines & Immunotherapeutics Apr 2016There are no Canadian immunization guidelines for children treated for malignancy. Guidelines do exist for patients who underwent hematopoietic stem cell transplant...
There are no Canadian immunization guidelines for children treated for malignancy. Guidelines do exist for patients who underwent hematopoietic stem cell transplant (HSCT), but they provide broad timeframes for initiating vaccination; there is no standard schedule. The optimal approach to immunization in these populations is unclear. We sought to describe immunization practices at Canadian Pediatric Hematology/Oncology centers. A 43-item online questionnaire was distributed to the 16 programs in the C(17) research network of pediatric hematology/oncology centers to capture information on timing and criteria for immunization of patients with acute lymphocytic leukemia (ALL) and those who have undergone HSCT. At each center, 1-2 physicians or pharmacists completed the survey to reflect center-wide immunization practices. Responses were received from 11/16 (69%) programs; 11 respondents reported on practices for patients with ALL and 9 reported on practices for patients who are post-HSCT. In 5/11 ALL programs (45%) re-immunization is recommended routinely after chemotherapy, starting 3-6 months post-chemotherapy. In HSCT programs, timing of pneumococcal conjugate vaccination (PCV) varied from 3 months post-HSCT (4 programs) to 12 months post-HSCT (4 programs). Live vaccines were administered 24 months post-HSCT in 8/9 programs. All HSCT programs considered graft-versus-host-disease and 7 considered discontinuation of immunosuppression in immunization decisions. Pediatric hematology/oncology programs were divided in regards to re-immunization of patients with ALL post-chemotherapy. After HSCT, timing of PCV administration varied, with 4 programs initiating immunization later than Canadian guidelines recommend (3-9 months post-HSCT). These findings suggest a need to standardize immunization practices in these populations.
Topics: Adolescent; Canada; Child; Female; Hematology; Hematopoietic Stem Cell Transplantation; Humans; Immunization; Immunocompromised Host; Immunosuppression Therapy; Male; Pediatrics; Practice Patterns, Physicians'; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Surveys and Questionnaires; Vaccines
PubMed: 26962702
DOI: 10.1080/21645515.2015.1115165 -
Molecular Cancer Jan 2023The acquisition of genetic abnormalities engendering oncogene dysregulation underpins cancer development. Certain proto-oncogenes possess several dysregulation...
The acquisition of genetic abnormalities engendering oncogene dysregulation underpins cancer development. Certain proto-oncogenes possess several dysregulation mechanisms, yet how each mechanism impacts clinical outcome is unclear. Using T-cell acute lymphoblastic leukemia (T-ALL) as an example, we show that patients harboring 5'super-enhancer (5'SE) mutations of the TAL1 oncogene identifies a specific patient subgroup with poor prognosis irrespective of the level of oncogene dysregulation. Remarkably, the MYB dependent oncogenic 5'SE can be targeted using Mebendazole to induce MYB protein degradation and T-ALL cell death. Of note Mebendazole treatment demonstrated efficacy in vivo in T-ALL preclinical models. Our work provides proof of concept that within a specific oncogene driven cancer, the mechanism of oncogene dysregulation rather than the oncogene itself can identify clinically distinct patient subgroups and pave the way for future super-enhancer targeting therapy.
Topics: Humans; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins; T-Cell Acute Lymphocytic Leukemia Protein 1; Basic Helix-Loop-Helix Transcription Factors; Mebendazole
PubMed: 36650499
DOI: 10.1186/s12943-022-01701-x -
Brazilian Journal of Medical and... Nov 2007MicroRNAs (miRNAs) are a class of small endogenous RNAs that play important regulatory roles by targeting mRNAs for cleavage or translational repression. miRNAs act in...
MicroRNAs (miRNAs) are a class of small endogenous RNAs that play important regulatory roles by targeting mRNAs for cleavage or translational repression. miRNAs act in diverse biological processes including development, cell growth, apoptosis, and hematopoiesis, suggesting their association with cancer. We determined the miRNA expression profile of chronic and acute lymphocytic leukemias (CLL and ALL) using the TaqMan MicroRNA Assays Human Panel (Applied Biosystems). Pooled leukemia samples were compared to pooled CD19+ samples from healthy individuals (calibrator) by the 2-DD Ct method. Total RNA input was normalized based on the Ct values obtained for hsa-miR-30b. The five most highly expressed miRNAs were miR-128b, miR-204, miR-218, miR-331, and miR-181b-1 in ALL, and miR-331, miR-29a, miR-195, miR-34a, and miR-29c in CLL. To our knowledge, this is the first report associating miR-128b, miR-204 and miR-331 to hematological malignancies. The miR-17-92 cluster was also found to be up-regulated in ALL, as previously reported for some types of lymphomas. The differences observed in gene expression levels were validated for miR-331 and miR-128b in ALL and CD19+ samples. These miRNAs were up-regulated in ALL, in agreement with our initial results. A brief target analysis was performed for miR-331. One of its putative targets, SOCS1, promotes STAT activation, which is a known mediator of cell proliferation and survival, suggesting the possibility of an association between miR-331 and these processes. This initial screening provided information on miRNA differentially expressed in normal and malignant B-cells that could suggest the potential roles of these miRNAs in hematopoiesis and leukemogenesis.
Topics: Case-Control Studies; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; MicroRNAs; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 17934639
DOI: 10.1590/s0100-879x2007001100003 -
American Journal of Hematology Jan 2016Chimeric antigen receptors (CARs) can be introduced into T-cells redirecting them to target specific tumor antigens. CAR-modified T cells targeting CD19 have shown... (Review)
Review
Chimeric antigen receptors (CARs) can be introduced into T-cells redirecting them to target specific tumor antigens. CAR-modified T cells targeting CD19 have shown remarkable activity against CD19+ malignancies including B cell acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphomas (NHL). Complete remission rates as high as 90% have been observed for patients with relapsed and refractory ALL and greater than 50% response rates have been seen in heavily pre-treated CLL and NHL. Excitingly, some remissions have been durable without any additional therapy, a finding which correlates with in-vivo T-cell persistence and B-cell aplasia. The major treatment related toxicities include B-cell aplasia, neurologic toxicities, and a potentially severe cytokine release syndrome. This review summarizes outcomes for patients treated with CD19-CAR T-cells while exploring the field's challenges and future directions.
Topics: Antibodies, Monoclonal; Antigens, CD19; Chimera; Disease-Free Survival; Gene Transfer Techniques; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Antigen, T-Cell; T-Lymphocytes
PubMed: 26574400
DOI: 10.1002/ajh.24238 -
Cancer Epidemiology Feb 2019To investigate an association between maternal prenatal exposure to several environmental factors and risk of childhood acute lymphocytic leukemia (ALL), and the...
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.
Topics: Adolescent; Adult; Case-Control Studies; Child; Child, Preschool; China; Environmental Exposure; Female; Hospitals; Humans; Infant; Infant, Newborn; Male; Maternal Exposure; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pregnancy; Prenatal Exposure Delayed Effects; Risk Factors; Surveys and Questionnaires; Young Adult
PubMed: 30579239
DOI: 10.1016/j.canep.2018.11.005 -
Iranian Journal of Allergy, Asthma, and... Oct 2019Acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) are common acute leukemia in adults and children, respectively. In these malignancies, chemotherapy is...
Acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) are common acute leukemia in adults and children, respectively. In these malignancies, chemotherapy is the main treatment strategy that fails in many cases and is usually associated with adverse effects on healthy cells. In this regard, the development of new therapies is essential. Monoclonal antibodies directed to the cell surface markers of leukemic blasts may have promising consequences with minimal toxic effects on normal cells. Since cluster of differentiation 45Ra (CD45Ra) and CD123 antigens, two considered surface markers of leukemic blasts in AML and ALL respectively, are overexpressed on AML and ALL blasts, CD34+ leukemic progenitors, and AML-LSCs in comparison with normal hematopoietic stem cells (HSCs), they were selected to be targeted; using specific monoclonal antibodies. In this project, CD45Ra+ cells and CD123+ cells were targeted by anti-CD45Ra and/or anti-CD123 monoclonal antibodies. Cytotoxicity effect and cell death induction was determined by 3-(4,5-dimethylthiazol-2-yl)-2-5-diphenyltetrazolium bromide (MTT) assay and flow cytometry. Changes in the expression profile of MCL1, cMyc, Survivin, Id1, and PIM1 genes were assessed by real-time PCR. Statistical analysis of the results showed effective antibody-mediated cytotoxicity and induction of apoptosis in KG1α (CD45Ra+) and Nalm6 (CD123+) cell lines. Also, a significant change in the expression level of some of the apoptosis-related genes was observed. According to the results of this study, it can be concluded that an effective targeting of AML and ALL cancerous cell lines can be performed by anti-CD45Ra and anti-CD123 monoclonal antibodies through their effector functions and apoptosis induction.
Topics: Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Apoptosis; Cell Line, Tumor; Cell Survival; Humans; Interleukin-3 Receptor alpha Subunit; Leukemia, Myeloid, Acute; Leukocyte Common Antigens; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transcriptome
PubMed: 32245312
DOI: 10.18502/ijaai.v18i6.2181 -
European Review For Medical and... 2014Although treatment results for adult acute lymphoblastic leukemia (ALL) have improved considerably in the past decades, treating adult patients with relapsed/refractory... (Review)
Review
Although treatment results for adult acute lymphoblastic leukemia (ALL) have improved considerably in the past decades, treating adult patients with relapsed/refractory acute lymphocytic leukemia (ALL) is still difficult. Adults with refractory/relapsed acute lymphocytic leukemia (ALL) processed to death rapidly associated with chemotherapy resistance, high mortality by reinduction, etc. Only 20% to 30% of those patients acquired complete remission (CR). Those patients are always of short duration unless an allogeneic stem cell transplant is feasible. Median survival is only ranging from 2 to 12 months. Therapeutic strategy on relapsed/refractory acute lymphocytic leukemia (ALL) is always a major therapeutic challenge bothering hematological researchers. Novel agents and unique therapeutic strategies have been developed in recent years. This review focuses on major clinical advances in the agents for refractory/relapsed ALL.
Topics: Adult; Female; Humans; Male; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Salvage Therapy; Young Adult
PubMed: 25268091
DOI: No ID Found -
MicrobiologyOpen Mar 2020Hematological malignancies are the most common type of pediatric cancers, and acute lymphocytic leukemia (ALL) is the most frequently occurring hematological malignancy...
Hematological malignancies are the most common type of pediatric cancers, and acute lymphocytic leukemia (ALL) is the most frequently occurring hematological malignancy during childhood. A major cause of mortality in leukemia is bloodstream infection (BSI). The aim of the current study was to explore the gut microbiota in ALL and its potential functional alterations. High-throughput sequencing was used to characterize the bacterial and fungal microbiota in feces and their predicted functional characteristics in a xenotransplant pediatric ALL mouse model. Our work shows that gut microbiota significantly changes in leukemia, which may result in functional alterations. This study may provide potential therapeutic or preventive strategies of BSI in ALL.
Topics: Animals; Biodiversity; Feces; Female; Gastrointestinal Microbiome; High-Throughput Nucleotide Sequencing; Metagenomics; Mice; Microbiota; Precursor Cell Lymphoblastic Leukemia-Lymphoma; RNA, Ribosomal, 16S
PubMed: 31884727
DOI: 10.1002/mbo3.982