MicroRNA‐326 and microRNA‐200c: Two novel biomarkers for diagnosis and prognosis of pediatric acute lymphoblastic leukemia

Abstract

Multidrug resistance (MDR) is considered as the major obstacle for treating pediatric acute lymphoblastic leukemia (ALL). MicroRNAs (miRNAs) are small non coding RNAs which may potentially regulate response to chemotherapy. In this study, total RNA was isolated from bone marrow samples of 46 children with de novo ALL and 16 controls. Quantitative reverse transcriptase polymerase chain reaction was used to investigate the expression profile of the predicted miRNAs; miR-326 and miR-200c, and their predicted targets ABCA2, and ABCA3 transporters. The presence of minimal residual disease was studied using PCR-SSCP (single-strand conformation polymorphism) 1 year after treatment. The association between the miRNA expression and drug resistance was analyzed statistically. Results showed a significant down-regulation of both miR-326 and miR-200c expressions in ALL patients compared with non-cancer controls (P = 0.0002, AUC = 0.813 and P = 0.035, AUC = 0.79, respectively). A considerable negative association between miR-326 expression and MDR was identified which could raise the risk of chemoresistance by 4.8- fold. The expression profiles of miR-326 and ABCA2 transporter were inversely correlated. Data revealed, a novel diagnostic role for miR-326 and miR-200c as potential biomarkers of pediatric ALL. Down-regulation of miR-326 was introduced, for the first time, as a prognostic factor for drug resistance in childhood ALL. To the best of our knowledge, this is the first time that ABCA2 transporter is proposed as a target gene for miR-326, through which it can exert its impact on drug resistance. These data may provide novel approaches to new therapeutics and diagnostics.

Role of non-coding RNA networks in leukemia progression, metastasis and drug resistance

“…In addition to ABCC144, miR-326 also negatively regulated other ABC family members such as ABCA2 and ABCA3, which are drug-resistance related genes [200]. However, the miR-326 expression is reported to be significantly downregulated in the multidrug resistance (MDR+) pediatric ALL patients compared to the (MRD-) group [27]. A recent study showed upregulation of miR-125b-2 cluster (Let-7c, miR-125b, and miR-99a) in leukemia patients with ETV6-RUNX1 + fusion gene expression.…”

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

“…Furthermore, we demonstrated downregulation of miR-335-3p in the chALL MDR patients (58 B-ALL and 6 T-ALL). Interestingly, our data revealed that, there is a possibly causative correlation between the downregulation of miR-326 and miR-335-3p, increased risk of drug resistance and ALL relapse, and upregulation of ABCA2 and ABCA3 transporters, respectively (97,106).…”

“…MicroRNAs, recently discovered non-coding endogenous single-stranded RNAs (composed of 19-24 nucleotides), show dysregulation during hematopoiesis and thereby have role in leukemogenesis (14,94). 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).…”

“…Some examples of oncogenic miRNAs in chALL are miR-203 and miR-125b. Some tumor suppressor miRNAs are miR-181a, miR-326, and miR-200c, which show frequently down-regulation in chALL (97,98). MicroRNA profiling can also be correlated with relevant clinical information, such as disease aggressiveness and metastatic potential, patient response to therapy, time-to-relapse and OS, and other clinical markers in chALL (101).…”

<p>Sal-Like Protein 4 Transcription Factor: A Significant Diagnostic Biomarker Involved in Childhood ALL Resistance and Relapse</p>

“…17 Moreover, in the AML patients, increased expression level of SALL4 results in drug resistance and poor prognosis through regulating the expression of the ATP-binding cassette (ABC) drug transports, such as ABCG2 and ABCA3. 9,18 Nevertheless, with the general lack of studies about SALL4 expression and its correlation with ABC transporter genes, there is little information about the role of this gene in the biological behavior of childhood ALL and its correlation with MDR and relapse.…”