Acute lymphoblastic leukemia is the most common type of childhood cancer worldwide. Mexico City has one of the highest incidences and mortality rates of this cancer. It has previously been recognized ...that chromosomal translocations are important in cancer etiology. Specific fusion genes have been considered as important treatment targets in childhood acute lymphoblastic leukemia (ALL). The present research aimed at the identification and characterization of novel fusion genes with potential clinical implications in Mexican children with acute lymphoblastic leukemia. The RNA-sequencing approach was used. Four fusion genes not previously reported were identified:
,
,
,
. Although a fusion gene is not sufficient to cause leukemia, it could be involved in the pathogenesis of the disease. Notably, these new translocations were found in genes encoding for hematopoietic transcription factors which are known to play an important role in leukemogenesis and disease prognosis such as
,
, and
. In addition, they may have an impact on the prognosis of Mexican pediatric patients with ALL, with the potential to be included in the current risk stratification schemes or used as therapeutic targets.
NK cells have unique attributes to react towards cells undergoing malignant transformation or viral infection. This reactivity is regulated by activating or inhibitory germline encoded receptors. An ...impaired NK cell function may result from an aberrant expression of such receptors, a condition often seen in patients with hematological cancers. Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer worldwide and NK cells have emerged as crucial targets for developing immunotherapies. However, there are important gaps concerning the phenotype and behavior of NK cells during emergence of ALL. In this study we analyze the phenotype and function of NK cells from peripheral blood in pediatric patients with ALL at diagnosis. Our results showed that NK cells exhibited an altered phenotype highlighted by a significant reduction in the overall expression and percent representation of activating receptors compared to age-matched controls. No significant differences were found for the expression of inhibitory receptors. Moreover, NK cells with a concurrent reduced expression in various activating receptors, was the dominant phenotype among patients. An alteration in the relative frequencies of NK cells expressing NKG2A and CD57 within the mature NK cell pool was also observed. In addition, NK cells from patients displayed a significant reduction in the ability to sustain antibody-dependent cellular cytotoxicity (ADCC). Finally, an aberrant expression of activating receptors is associated with the phenomenon of leukemia during childhood.
Background
B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most frequent pediatric cancer worldwide. Despite improvements in treatment regimens, approximately 20% of the cases cannot ...be cured, highlighting the necessity for identifying new biomarkers to improve the current clinical and molecular risk stratification schemes. We aimed to investigate whether
LINC00173
is a biomarker in ALL and to explore its expression level in other human cancer types.
Methods
A nested case–control study including Mexican children with BCP-ALL was conducted.
LINC00173
expression was evaluated by qRT-PCR using hydrolysis probes. To validate our findings, RNA-seq expression data from BCP-ALL and normal tissues were retrieved from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and Genotype-Tissue Expression (GTEx) repositories, respectively.
LINC00173
expression was also evaluated in solid tumors by downloading available data from The Cancer Genome Atlas (TCGA).
Results
A lower expression of
LINC00173
in BCP-ALL cases compared to normal subjects was observed (
p
< 0.05). ALL patients who carry the
TCF3/PBX1
fusion gene displayed lower expression of
LINC00173
in contrast to other BCP-ALL molecular subtypes (
p
< 0.04).
LINC00173
underexpression was associated with a high risk to relapse (HR = 1.946, 95% CI = 1.213–3.120) and die (HR = 2.073, 95% CI = 1.211–3.547). Patients with
TCF3/PBX1
and underexpression of
LINC00173
had the worst prognosis (DFS: HR = 12.24, 95% CI = 5.04–29.71; OS: HR = 11.19, 95% CI = 26–32). TCGA data analysis revealed that underexpression of
LINC00173
is also associated with poor clinical outcomes in six new reported tumor types.
Conclusion
Our findings suggest that
LINC00173
is a biomarker of poor prognosis in BCP-ALL and other types of cancer. We observed an association between the expression of
LINC00173
and
TCF3/PBX1
and the risk to relapse and die in BCP-ALL, which is worse in
TCF3/PBX1-
positive cases displaying underexpression of
LINC00173.
Experimental studies are needed to provide insight into the
LINC00173
and
TCF3/PBX
relationship.
Mexico City has one of the highest incidences of acute lymphoblastic leukemia (ALL) globally, with patients showing low survival, and high relapse rates. To gain more insight into the molecular ...features of B-ALL in Mexican children, we isolated CD10 + /CD19 + precursor B lymphoblasts from four bone marrow and nine peripheral blood samples of B-ALL patients using a fluorescence-activated cell sorting protocol. The global gene expression profile (BM vs PB) revealed 136 differentially expressed genes; 62 were upregulated (45.6%) and 74 were downregulated (54.4%). Pearson’s correlation coefficient was calculated to determine the similarity between pre-B lymphoblast populations. We selected 26 highly significant genes and validated 21 by RT-qPCR (
CNN3, STON2, CALN1, RUNX2, GADD45A, CDC45, CDC20, PLK1, AIDA, HCK, LY86, GPR65, PIK3CG, LILRB2, IL7R, TCL1A, DOCK1, HIST1H3G, PTPN14, CD72,
and
NT5E
)
.
The gene set enrichment analysis of the total expression matrix and the ingenuity pathway analysis of the 136 differentially expressed genes showed that the cell cycle was altered in the bone marrow with four overexpressed genes (
PLK1, CDC20, CDC45,
and
GADD45A
) and a low expression of
IL7R
and
PIK3CG,
which are involved in B cell differentiation. A comparative bioinformatics analysis of 15 bone marrow and 10 peripheral blood samples from Hispanic B-ALL patients collected by the TARGET program, corroborated the genes observed, except for
PIK3CG
. We conclude the Mexican and the Hispanic B-ALL patients studied present common driver alterations and histotype-specific mutations that could facilitate risk stratification and diagnostic accuracy and serve as potential therapeutic targets.
Background
The distribution of
RUNX1-RUNXT1
,
PML-RARA
,
CBFB-MYH11
,
BCR-ABL1
p210
, and
KMT2A-MLLT3
in the pediatric population with acute myeloid leukemia (AML) in many countries of Latin America ...is largely unknown. Therefore, we aimed to investigate the frequency of these fusion genes in children with
de novo
AML from Mexico City, which has one of the highest incidence rates of acute leukemia in the world. Additionally, we explored their impact in mortality during the first year of treatment.
Methods
We retrospectively analyzed the presence of
RUNX1-RUNXT1
,
PML-RARA
,
CBFB-MYH11
,
BCR-ABL1
p210
, and
KMT2A-MLLT3
by RT-PCR among 77 patients (<18 years) diagnosed with
de novo
AML between 2019 and 2021 in nine Mexico City hospitals.
Results
The overall frequency of the fusion genes was 50.7%;
RUNX1-RUNXT1
(22.1%) and
PML-RARA
(20.8%) were the most prevalent, followed by
CBFB-MYH11
(5.2%) and
BCR-ABL1
p210
(2.4%).
KMT2A-MLLT3
was not detected. Patients with
PML-RARA
showed the lowest survival with high early mortality events. However, more studies are required to evaluate the impact of analyzed fusion genes on the overall survival of the Mexican child population with AML.
Conclusion
The pediatric population of Mexico City with AML had frequencies of
AML1-ETO
,
PML-RARA
,
CBFB-MYH11
, and
BCR-ABL1
p210
similar to those of other populations around the world. Patients with
BCR-ABL1
p210
and
CBFB-MYH11
were few or did not die, while those with
MLL-AF9
was not detected. Although patients with
PML-RARA
had a low survival and a high early mortality rate, further studies are needed to determine the long-term impacts of these fusion genes on this Latino population.
Background and Aims Acute lymphoblastic leukemia (ALL) is the most common childhood cancer worldwide. Mexican patients have high mortality rates, low frequency of good prognosis biomarkers (i.e., ...ETV6-RUNX1 ) and a high proportion is classified at the time of diagnosis with a high risk to relapse according to clinical features. In addition, very early relapses are more frequently observed than in other populations. The aim of the study was to identify new potential biomarkers associated with very early relapse in Mexican ALL children through transcriptome analysis. Methods Microarray gene expression profiling on bone marrow samples of 54 pediatric ALL patients, collected at time of diagnosis and/or at relapse, was performed. Eleven patients presented relapse within the first 18 months after diagnosis. Affymetrix Human Transcriptome Array 2.0 (HTA 2.0) was used to perform gene expression analysis. Annotation and functional enrichment analyses were carried out using Gene Ontology, KEGG pathway analysis and Ingenuity Pathway Analysis tools. Results BLVRB, ZCCHC7, PAX5, EBF1, TMOD1 and BLNK were differentially expressed (fold-change >2.0 and p value <0.01) between relapsed and non-relapsed patients. Functional analysis of abnormally expressed genes revealed their important role in cellular processes related to the development of hematological diseases, cancer, cell death and survival and in cell-to-cell signaling interaction. Conclusions Our data support previous findings showing the relevance of PAX5 , EBF1 and ZCCHC7 as potential biomarkers to identify a subgroup of ALL children in high risk to relapse.
Abstract 4301
Acute lymphoblastic leukemia (ALL) is the most common type of childhood malignancy worldwide and Mexico has one of the highest reported incidence rates at 49.5 cases per million. ...Infections have been strongly suggested to be a causative factor for ALL; however, the identity of the agent involved is presently unknown. In many animal species, members of the Retroviridae family are responsible for leukemias. The murine mammary tumor virus (MMTV) is associated with leukemia and breast cancer in mice and has been suggested to be associated with human breast cancer. The T-cell lymphotropic virus 1 (HTLV1) is the causative factor of adult T cell leukemia. In this study, we assessed whether MMTV and HTLV1/2 are also involved in childhood ALL.
95 children from four Mexican states and Mexico City with untreated B cell ALL, aged 8 months to 16 years were included in the study. Bone marrow samples were screened using conventional PCR assays. Because the mutation rate is considerably high in retroviruses, false negatives due to inadequate primer recognition are likely. To avoid that, two sets of primers targeting different regions of the retroviral genomes were used and the PCR annealing temperatures were set at ≤ 55 °C. Also, the primers used in these assays had low similarity with human endogenous retroviral sequences to exclude false positives. The sensitivity of the MMTV PCR reactions was determined with plasmid DNA containing a region of the MMTV env gene and genomic DNA from CD1 mice spleens and for HTLV1/2 with DNA from the MJ cell line. Because ALL is defined by a frequency of at least 25% of leukemic blasts, the PCR sensitivities were set to detect in samples at least this frequency of infected cells. A nested PCR was also designed to confirm negative cases.
None of the samples were positive to any of the retroviruses. The study's statistical power to detect one or more MMTV or HTLV1/2 positive samples from our study population (N=95) for 20%, 15% or 10% hypothesized proportions of cases with genomic integration was quite high.
Our study does not support the involvement of MMTV or HTLV1/2 in the etiology of childhood acute lymphoblastic leukemia in samples from Mexico.
This work was partially funded by the Mexican Institute of Social Security through its program “Apoyo Financiero para el Desarrollo de Protocolos de Investigación en Salud en el IMSS” and by the Graduate Program of Doctor Degree in Biomedical Sciences, Medicine Faculty, National Autonomous University of Mexico, Mexico City, Mexico.
No relevant conflicts of interest to declare.
A heterogeneous geographic distribution of childhood acute lymphoblastic leukemia (ALL) cases has been described, possibly, related to the presence of different environmental factors. The aim of the ...present study was to explore the geographical distribution of childhood ALL cases in Greater Mexico City (GMC).
A population-based case-control study was conducted. Children <18 years old, newly diagnosed with ALL and residents of GMC were included. Controls were patients without leukemia recruited from second-level public hospitals, frequency-matched by sex, age, and health institution with the cases. The residence address where the patients lived during the last year before diagnosis (cases) or the interview (controls) was used for geolocation. Kulldorff's spatial scan statistic was used to detect spatial clusters (SCs). Relative risks (RR), associated p-value and number of cases included for each cluster were obtained.
A total of 1054 cases with ALL were analyzed. Of these, 408 (38.7%) were distributed across eight SCs detected. A relative risk of 1.61 (p<0.0001) was observed for the main cluster. Similar results were noted for the remaining seven ones. Additionally, a proximity between SCs, electrical installations and petrochemical facilities was observed.
The identification of SCs in certain regions of GMC suggest the possible role of environmental factors in the etiology of childhood ALL.
Background and Aims Occupational exposure of parents to carcinogens is of great interest in the etiology of leukemias. Evidence of the impact of such exposure on infants or small children is scarce. ...Here we estimated whether occupational exposure of parents to carcinogens could be a risk factor for leukemias in their children. Methods Cases of acute leukemia (AL) in infants ≤24 months old diagnosed in Mexico City (1998–2013) were included in a population-based, case-control study. Each of the 195 cases was matched with at least one healthy child ( n = 369). For each of four exposure windows studied, the degree of exposure to carcinogens was determined for both parents by using a validated occupational exposure index. An unconditional logistic regression was carried out. Results Odds ratios (OR) and the 95% confidence intervals (CI) of the overall occupational exposure for parents during the four exposure windows indicated no association with risk of AL in their children. Pre-conception, the OR by the father 0.77 (0.49–1.21), by the mother 1.03 (0.50–2.11); during pregnancy, father 0.66 (0.38–1.15), mother 1.79 (0.46–6.90); during breastfeeding, father 0.75 (0.43–1.30), mother 0.96 (0.21–4.30); and after birth, father 0.74 (0.45–1.22), mother 0.90 (0.24–3.32). The statistical power of the sample size to identify an OR ≥2 and an exposure of ≥10% among controls was 78%. Conclusions These data support the idea that parents’ occupational exposure during any of the periods studied was not a risk factor contributing to the etiology of AL in infants ≤24 months of age.
Mexico City has one of the highest incidences and mortality rates of acute lymphoblastic leukemia (ALL) in the world and a high frequency of early relapses (17%) and early mortality (15%). Otherwise, ...childhood overweight and obesity are reaching epidemic proportions. They have been associated with poor outcomes in children with ALL. The aim of present study was to identify if overweight and obesity are predictors of early mortality and relapse in Mexican children with ALL.
A multicenter cohort study was conducted. ALL children younger than 15 years old were included and followed-up during the first 24 months after diagnosis. Overweight and obesity were classified according World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) criteria. Early mortality and early relapses were the main outcomes.
A total of 1070 children were analyzed. Overweight/obesity at diagnosis were predictors of early mortality (WHO: HR = 1.4, 95%CI:1.0-2.0; CDC: HR = 1.6, 95%CI:1.1-2.3). However, no associations between overweight (WHO: HR = 1.5, 95%CI:0.9-2.5; CDC: HR = 1.0; 95% CI:0.6-1.6) and obesity (WHO: HR = 1.5, 95%CI:0.7-3.2; CDC: HR = 1.4; 95%CI:0.9-2.3) with early relapse were observed.
Overweight and obese patients embody a subgroup with high risk of dying during leukemia treatment.
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