Potential roles of microRNA‐29a in the molecular pathophysiology of T‐cell acute lymphoblastic leukemia

Abstract

Recent evidence has shown that deregulated expression of members of the microRNA-29 (miR-29) family may play a critical role in human cancer, including hematological malignancies. However, the roles of miR-29 in the molecular pathophysiology of T-cell acute lymphoblastic leukemia (T-ALL) has not been investigated. Here, we show that lower levels of miR-29a were significantly associated with higher blast counts in the bone marrow and with increased disease-free survival in T-ALL patients. Furthermore, miR-29a levels are extremely reduced in T-ALL cells compared to normal T cells. Microarray analysis following introduction of synthetic miR-29a mimics into Jurkat cells revealed the downregulation of several predicted targets (CDK6, PXDN, MCL1, PIK3R1, and CXXC6), including targets with roles in active and passive DNA demethylation (such as DNMT3a, DNMT3b, and members of the TET family and TDG). Restoring miR-29a levels in Jurkat and Molt-4 T-ALL cells led to the demethylation of many genes commonly methylated in T-ALL. Overall, our results suggest that reduced miR-29a levels may contribute to the altered epigenetic status of T-ALL, highlighting its relevance in the physiopathology of this disease.

Prognostic value of the MicroRNA‐29 family in multiple human cancers: A meta‐analysis and systematic review

“…Overall survival data were extracted from 18 studies. 12,13,[17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] Subsequent meta-analysis with a random-effect model generated…”

Transcriptome profiling of the developing male germ line identifies the miR-29 family as a global regulator during meiosis

“…60,61 We did not identify enrichment in categories such as response to DNA damage or methylation, 2 processes miR-29 has been previously implicated in, but did identify direct targets involved in DNA damage -Ing4 and Parg (Table SXIIIyellow-coded genes)and methylation -Gm17296, Jarid2, and Tet3 (Table SXIII blue-coded genes); the ability of the miR-29 family to regulate Tet3 has been shown in vitro. 62 Notably, we did not have enough intron and exon counts to determine if the denovo methyltransferase, Dnmt3a, a well-studied target of miR-29, 63,64 was changing post-transcriptionally. It was, however, significantly downregulated in meiotic cells as compared to post-meiotic cells (log 2 fold change D ¡5.1, p D 4.0 £ 10 -34 ).…”

A gene expression signature for defining aggressive phenotype and prognosis in intermediate-risk acute myeloid leukemia

“…It is one of the target genes of miR-29a. Ectopic overexpression of miR-29a promoted self-renewal of myeloid progenitors and led to AML ultimately in mouse model (Oliveira et al 2015). What's more, PXDN were diminished in AML (Desmond et al 2007 Researches on FLJ42875 were limited.…”