MicroRNAs expression signatures are associated with lineage and survival in acute leukemias

Abstract

MicroRNAs (miRNAs) are small (~22 nucleotide) non-coding RNAs whose altered expression has been associated with various types of cancers, including leukemia. In the present study, we conducted a quantitative PCR (qPCR) analysis of expression of 23 human precursor miRNAs in bone marrow specimens of 85 Chinese primary leukemia patients, including 53 acute myeloid leukemia (AML) and 32 acute lymphoblastic leukemia (ALL) cases. We show that 16 miRNAs were differentially expressed between AMLs and ALLs; Of them, eight were previously reported (i.e., miR-23a, miR-27a/b, miR-128a, miR-128b, miR-221, miR-222, miR-223, and let-7b) and eight were newly identified (i.e., miR-17, miR-20a, miR-29a/c, miR-29b, miR-146a, miR-150, miR-155, and miR-196b). More importantly, through correlating miRNA expression signatures with outcome of patients, we further show that expression signatures of a group of miRNAs are associated with overall survival of patients. Of them, three (i.e., miR-146a, miR-181a/c, and miR-221), five (i.e., miR-25, miR-26a, miR-29b, miR-146a, and miR-196b), and three (i.e., miR-26a, miR-29b, and miR-146a) miRNAs are significantly associated with overall survival (P<0.05) of the 32 ALL, 53 AML, and 40 non-M3 AML patients, respectively. Particularly, the expression signature of miR-146a is significantly inversely correlated with overall survival of both ALL and AML patients. The prognostic significance of miR-146a in AML has been confirmed further in an independent study of 61 Chinese new AML patient samples. We also identified 622 putative target genes of miR-146a that are predicted by at least three out of the five major prediction programs (i.e., TragetScan, PicTar, miRanda, miRBase Targets, and PITA); Through gene ontology analysis, we found that these genes were particularly enriched (2–9 fold higher than expected by chance) in the GO categories of “negative regulation of biology processes”, “negative regulation of cellular processes”, “apoptosis”, and “cell cycle”, which may be related to the association of miR-146a with poor survival.

NRF2-driven miR-125B1 and miR-29B1 transcriptional regulation controls a novel anti-apoptotic miRNA regulatory network for AML survival

“…Of particular interest from this group is miR-222, miR-221 and miR223, which have been shown to be highly expressed in AML compared with other leukaemias. 37 Moreover, we also noted that high NRF2 activity caused a decrease in the expression of miRNAs, which includes miR-154, miR146a and miR-181B. All these miRNAs have been shown to be of interest in AML with miR-146a being shown to have low expression in AML, which correlates with high expression of its target gene CXCR4, 38 which in a separate study has been shown to be regulated by NRF2 in human HSC.…”

Prognostic Role of microRNA-155 in Various Carcinomas: Results from a Meta-Analysis

“…After manually screening the titles, abstracts and key data, 259 records were excluded for not meeting the criteria listed above. Of the 28 reports selected for the systematic review, 12 studies were excluded in the final meta-analysis for lack of key HR value [21][22][23][24][25][26][27][28][29][30][31][32]. The excluded 12 studies commonly focused on other miRNAs and did not analyze the miR-155 data individually.…”

Clinical and prognostic significance of miR-155 and miR-146a expression levels in formalin-fixed/paraffin-embedded tissue of patients with diffuse large B-cell lymphoma

“…Down-regulation of miR-146a expression by the c-Myc oncogenic transcription factor has been previously observed in human and mouse B-cell lymphomas (30). Recent studies have evaluated the expression levels of miR-146a in acute lymphocytic leukemia and chronic lymphocytic leukemia (31)(32)(33). Their findings imply that miR-146a expression involved in deletion or amplification may be cell type-specific.…”