MicroRNA expression profiles discriminate childhood T‐ from B‐acute lymphoblastic leukemia

Abstract

MicroRNAs (miRNAs) play a critical role on biological and cellular processes; the search for functional markers may be of importance for differential diagnosis, prognosis, and development of new therapeutic regimens. In this context, we evaluated the bone marrow miRNA profile of Brazilian children exhibiting T‐ or B‐cell acute lymphoblastic leukemia (T‐ALL or B‐ALL), using massive parallel sequencing, using the HiSeq 2500 platform (Illumina). The differential expression analysis was conducted considering a leave‐one‐out approach and FDR ≤ 0.05. Machine learning algorithms were applied to search for the disease subset biomarkers. Target prediction, functional enrichment, and classification of biological categories were also performed. Sixteen miRNAs were differentially expressed between T‐ and B‐ALL, of which 10 (miR‐708‐5p, miR‐497‐5p, miR‐151a‐5p, miR‐151b, miR‐371b‐5p, miR‐455‐5p, miR‐195‐5p, miR‐1266‐5p, miR‐574‐5p, and miR‐425‐5p) were downregulated and six (miR‐450b‐5p, miR‐450a‐5p, miR‐542‐5p, miR‐424‐5p, miR‐629‐5p, and miR‐29c‐5p) were upregulated in childhood T‐ALL. These miRNAs may be used for distinguishing childhood lymphoblastic leukemia subtypes, since it provided the clear separation of patients in these two distinct groups. Six relevant biological pathways were identified according to their role in leukemia, namely, viral carcinogenesis, cell cycle, and B‐cell receptor signaling pathways for induced miRNAs and TGF‐beta signaling, apoptosis, and NF‐kappa B signaling for the repressed miRNAs, of which several miRNA gene targets participate in cell differentiation and hematopoiesis processes. Machine learning analysis pointed out miR‐29c‐5p expression as the best discriminator between childhood T‐ and B‐ALL, which is involved in calcium signaling, critical for B‐cell lymphocyte fate. Further studies are needed to assure the role of the 16 miRNAs and miR‐29c‐5p on acute lymphoblastic leukemia subtypes and on disease prognosis.

miRNAs in Acute Lymphoblastic Leukemia: Diagnosis, Prognosis and Target Therapeutic

“…However, a machine learning analysis showed that miR-29c-5p, which is involved in calcium signaling, is critical for B-cell lymphocyte fate. So, it is the best discriminator between childhood T-and B-ALL [40].…”

“…A study in Brazilian children with T-or B-cell acute lymphoblastic leukemia (T-ALL or B-ALL) evaluated a bone marrow miRNAs profile that may be used for distinguishing childhood lymphoblastic leukemia subtypes [40]. The authors mention that miR-708-5p, miR-497-5p, miR-151a-5p, miR-151b, miR-371b-5p, miR-455-5p, miR-195-5p, miR-1266-5p, miR-574-5p, miR-425-5p downregulated and miR-450b-5p, miR-450a-5p, miR-542-5p, miR-424-5p, miR-629-5p, miR-29c-5p upregulated in childhood T-ALL may be used for distinguishing childhood T-and B-ALL subtypes.…”

Drug Resistance Biomarkers and Their Clinical Applications in Childhood Acute Lymphoblastic Leukemia

“…These micro markers have proven to be very promising chALL biomarkers and have widespread clinical applications because of their stability and resistance to degradation in not only blood, but also various biological specimens (such as tissue, sputum, stool and formalin-fixed paraffin-embedded (FFPE) specimens), easily measured, and most importantly, their quantities correlates with the presence of the malignancy or with clinically relevant malignancy features (8,14,(95)(96)(97). Recent studies have revealed that extracellular circulating miRNA levels in secreted membrane vesicles (microvesicles and exosomes), blood serum, and other body fluids can be used as biomarkers to diagnose, classify and predict prognosis of chALL (96,(98)(99)(100)(101). miRNA expression dysregulation in cancers is because of different mechanisms, such as deletion or amplification of miRNA related genes, abnormal transcriptional control of miRNAs, epigenetic dysregulation and defects in the biogenesis machinery of miRNA (102).…”

“…Due to the promising characteristics of high stability, low cost, possibility of repeated sampling and noninvasiveness, circulating biomarkers have received extensive attention in molecular medicine nowadays. Compelling evidences have shown that these types of biomarkers are measurable in secreted membrane vesicles (microvesicles and exosomes), blood serum, and other body fluids and can be used as biomarkers to diagnose, classify, follow-up and predict prognosis in chALL (96,(98)(99)(100)(101). It has been suggested that extracellular circulating biomarkers play an important role in intracellular communication in both paracrine and endocrine manners (101).…”

Aberrant Chloride Intracellular Channel 4 Expression Is Associated With Adverse Outcome in Cytogenetically Normal Acute Myeloid Leukemia

“…MiR-146b could delay the aggressiveness and progression of T-ALL (29). miR-1266 was downregulated in childhood T-ALL and might be used to distinguish childhood ALL subtypes (30).…”