Transcriptome Analysis in Mexican Adults with Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) represents around 25% of adult acute leukemias. Despite the increasing improvement in the survival rate of ALL patients during the last decade, the heterogeneous clinical and molecular features of this malignancy still represent a major challenge for treatment and achieving better outcomes. To identify aberrantly expressed genes in bone marrow (BM) samples from adults with ALL, transcriptomic analysis was performed using Affymetrix Human Transcriptome Array 2.0 (HTA 2.0). Differentially expressed genes (DEGs) (±2-fold change, p-value < 0.05, and FDR < 0.05) were detected using the Transcriptome Analysis Console. Gene Ontology (GO), Database for Annotation, Visualization, and Integrated Discovery (DAVID), and Ingenuity Pathway Analysis (IPA) were employed to identify gene function and define the enriched pathways of DEGs. The protein-protein interactions (PPIs) of DEGs were constructed. A total of 871 genes were differentially expressed, and DNTT, MYB, EBF1, SOX4, and ERG were the top five up-regulated genes. Meanwhile, the top five down-regulated genes were PTGS2, PPBP, ADGRE3, LUCAT1, and VCAN. An association between ERG, CDK6, and SOX4 expression levels and the probability of relapse and death was observed. Regulation of the immune system, immune response, cellular response to stimulus, as well as apoptosis signaling, inflammation mediated by chemokines and cytokines, and T cell activation were among the most altered biological processes and pathways, respectively. Transcriptome analysis of ALL in adults reveals a group of genes consistently associated with hematological malignancies and underscores their relevance in the development of ALL in adults.

MiRNAs in Hematopoiesis and Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is the most common kind of pediatric cancer. Although the cure rates in ALL have significantly increased in developed countries, still 15-20% of patients relapse, with even higher rates in developing countries. The role of non-coding RNA genes as microRNAs (miRNAs) has gained interest from researchers in regard to improving our knowledge of the molecular mechanisms underlying ALL development, as well as identifying biomarkers with clinical relevance. Despite the wide heterogeneity reveled in miRNA studies in ALL, consistent findings give us confidence that miRNAs could be useful to discriminate between leukemia linages, immunophenotypes, molecular groups, high-risk-for-relapse groups, and poor/good responders to chemotherapy. For instance, miR-125b has been associated with prognosis and chemoresistance in ALL, miR-21 has an oncogenic role in lymphoid malignancies, and the miR-181 family can act either as a oncomiR or tumor suppressor in several hematological malignancies. However, few of these studies have explored the molecular interplay between miRNAs and their targeted genes. This review aims to state the different ways in which miRNAs could be involved in ALL and their clinical implications.

Underexpression of LINC00173 in TCF3/PBX1-Positive Cases Is Associated With Poor Prognosis in Children With B-Cell Precursor Acute Lymphoblastic Leukemia.

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.

Promising genes and variants to reduce chemotherapy adverse effects in acute lymphoblastic leukemia.

Almost two decades ago, the sequencing of the human genome and high throughput technologies came to revolutionize the clinical and therapeutic approaches of patients with complex human diseases. In acute lymphoblastic leukemia (ALL), the most frequent childhood malignancy, these technologies have enabled to characterize the genomic landscape of the disease and have significantly improved the survival rates of ALL patients. Despite this, adverse reactions from treatment such as toxicity, drug resistance and secondary tumors formation are still serious consequences of chemotherapy, and the main obstacles to reduce ALL-related mortality. It is well known that germline variants and somatic mutations in genes involved in drug metabolism impact the efficacy of drugs used in oncohematological diseases therapy. So far, a broader spectrum of clinically actionable alterations that seems to be crucial for the progression and treatment response have been identified. Although these results are promising, it is necessary to put this knowledge into the clinics to help physician make medical decisions and generate an impact in patients' health. This review summarizes the gene variants and clinically actionable mutations that modify the efficacy of antileukemic drugs. Therefore, knowing their genetic status before treatment is critical to reduce severe adverse effects, toxicities and life-threatening consequences in ALL patients.

Transcriptome Analysis Identifies LINC00152 as a Biomarker of Early Relapse and Mortality in Acute Lymphoblastic Leukemia.

Evidence showing the role of long non-coding RNAs (lncRNAs) in leukemogenesis have emerged in the last decade. It has been proposed that these genes can be used as diagnosis and/or prognosis biomarkers in childhood acute lymphoblastic leukemia (ALL). To know if lncRNAs are associated with early relapse and early mortality, a microarray-based gene expression analysis in children with B-lineage ALL (B-ALL) was conducted. Cox regression analyses were performed. Hazard ratios (HR) and 95% confidence intervals (95% CI) were calculated. LINC00152 and LINC01013 were among the most differentially expressed genes in patients with early relapse and early mortality. For LINC00152 high expression, the risks of relapse and death were HR: 4.16 (95% CI: 1.46-11.86) and HR: 1.99 (95% CI: 0.66-6.02), respectively; for LINC01013 low expression, the risks of relapse and death were HR: 3.03 (95% CI: 1.14-8.05) and HR: 6.87 (95% CI: 1.50-31.48), respectively. These results were adjusted by NCI risk criteria and chemotherapy regimen. The lncRNA-mRNA co-expression analysis showed that LINC00152 potentially regulates genes involved in cell substrate adhesion and peptidyl-tyrosine autophosphorylation biological processes. The results of the present study point out that LINC00152 could be a potential biomarker of relapse in children with B-ALL.

Long Non-Coding RNA and Acute Leukemia.

Acute leukemia (AL) is the main type of cancer in children worldwide. Mortality by this disease is high in developing countries and its etiology remains unanswered. Evidences showing the role of the long non-coding RNAs (lncRNAs) in the pathophysiology of hematological malignancies have increased drastically in the last decade. In addition to the contribution of these lncRNAs in leukemogenesis, recent studies have suggested that lncRNAs could be used as biomarkers in the diagnosis, prognosis, and therapeutic response in leukemia patients. The focus of this review is to describe the functional classification, biogenesis, and the role of lncRNAs in leukemogenesis, to summarize the evidence about the lncRNAs which are playing a role in AL, and how these genes could be useful as potential therapeutic targets.

Gene Expression Profiling of Acute Lymphoblastic Leukemia in Children with Very Early Relapse.

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.