Distinct power of bone marrow microRNA signatures and tumor suppressor genes for early detection of acute leukemia

BackgroundAcute leukemia involving lymphocytic and myeloid cells is cancer with a high mortality rate. Swift and timely diagnosis might be a potential approach to improving patient prognosis and survival. The microRNA (miRNA) signatures are emerging nowadays for their promising diagnostic potential. MiRNA levels from bone marrow can be used as prognostic biomarkers.MethodsThe current study was designed to evaluate if the microRNAs and tumor suppressor genes (TSGs) profiling of hematopoietic bone marrow could help in acute leukemia early detection. Also, we assessed the DNA methyltransferase 3A (DNMT3A) expression and its possible epigenetic effects on miRNAs plus TSGs expression levels. The expression levels of ten miRNAs and four TSGs involved in acute lymphocytic leukemia (ALL) as well as acute myeloid leukemia (AML) were quantified in 43 and 40 bone marrow samples of ALL and AML patients in comparison with cancer-free subjects via real-time quantitative PCR (RT-qPCR). The receiver-operating-characteristic (ROC) analysis of miRNAs was performed in the study groups. Further, the correlation between the DNMT3A and TSGs was calculated.ResultsSignificant differences were detected in the bone marrow expression of miRNAs and TSGs (P < 0.05) between acute leukemia patients and healthy group. ROC analysis confirmed the ability of miR-30a, miR-101, miR-132, miR-129, miR-124, and miR-143 to discriminate both ALL and AML patients with an area under the ROC curve of ≥ 0.80 (P < 0.001) and high accuracy. The correlation between DNMT3A and P15/P16 TSGs revealed that DNMT3A plays a vital role in epigenetic control of TSGs expression. Our findings indicated that the downregulation of bone marrow miRNAs and TSGs was accompanied by acute leukemia development.ConclusionsThe authors conclude that this study could contribute to introducing useful biomarkers for acute leukemia diagnosis.

Distinct power of bone marrow microRNA signatures and tumor suppressor genes for early detection of acute leukemia.

BACKGROUND: Acute leukemia involving lymphocytic and myeloid cells is cancer with a high mortality rate. Swift and timely diagnosis might be a potential approach to improving patient prognosis and survival. The microRNA (miRNA) signatures are emerging nowadays for their promising diagnostic potential. MiRNA levels from bone marrow can be used as prognostic biomarkers. METHODS: The current study was designed to evaluate if the microRNAs and tumor suppressor genes (TSGs) profiling of hematopoietic bone marrow could help in acute leukemia early detection. Also, we assessed the DNA methyltransferase 3A (DNMT3A) expression and its possible epigenetic effects on miRNAs plus TSGs expression levels. The expression levels of ten miRNAs and four TSGs involved in acute lymphocytic leukemia (ALL) as well as acute myeloid leukemia (AML) were quantified in 43 and 40 bone marrow samples of ALL and AML patients in comparison with cancer-free subjects via real-time quantitative PCR (RT-qPCR). The receiver-operating-characteristic (ROC) analysis of miRNAs was performed in the study groups. Further, the correlation between the DNMT3A and TSGs was calculated. RESULTS: Significant differences were detected in the bone marrow expression of miRNAs and TSGs (P < 0.05) between acute leukemia patients and healthy group. ROC analysis confirmed the ability of miR-30a, miR-101, miR-132, miR-129, miR-124, and miR-143 to discriminate both ALL and AML patients with an area under the ROC curve of ≥ 0.80 (P < 0.001) and high accuracy. The correlation between DNMT3A and P15/P16 TSGs revealed that DNMT3A plays a vital role in epigenetic control of TSGs expression. Our findings indicated that the downregulation of bone marrow miRNAs and TSGs was accompanied by acute leukemia development. CONCLUSIONS: The authors conclude that this study could contribute to introducing useful biomarkers for acute leukemia diagnosis.

Expression analysis of NF-κB-associated long noncoding RNAs in peripheral blood mononuclear cells from relapsing-remitting multiple sclerosis patients.

Long noncoding RNAs (lncRNAs) as potential disease biomarkers might be related to severe course of multiple sclerosis (MS). We evaluated expression levels of NF-κB-associated lncRNAs including HOTAIR, THRIL, H19, NKILA, and ANRIL; as well as expression of IL-6, TNF-α and MMP9, in peripheral blood mononuclear cells (PBMCs) from 60 relapse-remitting MS (RRMS) patients. At relapse phase of RRMS, up-regulation of ANRIL and H19 was positively correlated with the overexpression of IL-6; high levels of THRIL and HOTAIR was positively correlated with increased levels of TNF-α and MMP9, respectively; however, the NKILA expression was negatively correlated with the expression of TNF-α.

miR-455-5p downregulation promotes inflammation pathways in the relapse phase of relapsing-remitting multiple sclerosis disease.

MicroRNA-455-5p (miR-455-5p) seems to have an anti-inflammatory role in the immune system since its expression is induced by IL-10 cytokine. Multiple sclerosis (MS) is a chronic demyelinating neurodegenerative disease of the central nervous system that is caused by an autoimmune inflammatory attack against the myelin insulation of neurons. The expression level of miR-455-5p and its role in MS pathogenesis has yet to be elucidated. We found that miR-455-5p expression was highly correlated with disease severity in MS patients. miR-455-5p expression inversely correlates with its inflammatory-predicted targets (MyD88 and REL) in relapse- and remitting-phase patients. Luciferase assays confirm that MyD88 and REL are direct targets of miR-455-5p. This study represents the first report of the miR-455-5p acts as an anti-inflammatory role in MS, at least partially through targeting MyD88 and REL. This study may provide important information for the use of miR-455-5p as a novel strategy to improve the severity of disease and control inflammation and attack in MS patients.

Increased expression of mir-301a in PBMCs of patients with relapsing-remitting multiple sclerosis is associated with reduced NKRF and PIAS3 expression levels and disease activity.

Most of the multiple sclerosis (MS) patients are initially diagnosed with relapsing remitting multiple sclerosis (RRMS). Th17 cells and macrophages have been shown to play critical roles in pathogenesis of MS and initiation of CNS tissue damage. MiR-301a have recently been exposed as an activator of STAT3 in Th17 cells as well as an activator of NF-κB in macrophages by targeting PIAS3 and NKRF correspondingly. However, the possible role of miR-301a in RRMS has not yet been elucidated. Herewith, for the first time, we have studied the expression of miR-301a, NKRF and PIAS3 by quantitative real-time PCR and western blotting method in peripheral blood mononuclear cells (PBMCs) of 71 RRMS patients, including two groups of patients in relapse phase (n = 44) and a group of remitting phase patients (n = 28) in comparison to healthy volunteers (n = 28). In this work, we demonstrate a significant upregulation of miR-301a in relapse phase of MS patients compared to healthy controls and remitting phase patients (P < .05). Our findings also showed a striking decrease of NKRF and PIAS3 expression in relapse phase patients, in contrast to miR-301a and, NF-κB and STAT3 downstream genes (SKA2 and RORc) (P < .05). Subsequently, using luciferase reporter system we confirmed that miR-301a directly targets the mRNA encoding PIAS3 and NKRF proteins. We also showed that miR-301a increasing expression is correlated with down-regulation of PIAS3 and NKRF expression in RRMS patients. Our findings suggest that miR-301a, PIAS3 and NKRF play crucial roles in RRMS and could be considered as promising therapeutic targets.

Interleukin 4 inhibition as a potential therapeutic in pemphigus.

Pemphigus is an autoimmune bullous skin disease that results from desmosomal protein desmoglein 3 and 1 loss in pemphigus vulgaris and foliaceus, respectively. It can be considered as a Th2-dominant disease over-expressed by Th2 cell cytokines. Interleukin (IL)-4 is a key cytokine which can exacerbate Th2 over-expression in addition to isotype switching to immunoglobin (Ig)G1 and IgG4 that are responsible for desmoglein loss. Elevation of IL-4 level has also been reported in various studies. Considering the important role of IL-4 in severe phase of pemphigus and lack of effective and safeness therapy for this potentially fatal disease, anti-IL-4 therapy was introduced as a potential curative for pemphigus disease. This study reviewed all studies about any roles of IL-4 that can directly and indirectly be played in the development of pemphigus and IL-4 inhibition with interferons and dupilumab therapy were introduced as a novel pemphigus treatment for patients who are in relapse phase of the disease. Dupilumab was also introduced as a possible treatment for patients with severe pemphigus. It can directly inhibit IL-4 by targeting IL-4 α-chain receptor. IL-4 inhibition can lead to the creation of Th1:Th2 balance by various pathways, discussed in this study.