Characterization of a set of tumor suppressor microRNAs in T cell acute lymphoblastic leukemia

Abstract

The posttranscriptional control of gene expression by microRNAs (miRNAs) is highly redundant, and compensatory effects limit the consequences of the inactivation of individual miRNAs. This implies that only a few miRNAs can function as effective tumor suppressors. It is also the basis of our strategy to define functionally relevant miRNA target genes that are not under redundant control by other miRNAs. We identified a functionally interconnected group of miRNAs that exhibited a reduced abundance in leukemia cells from patients with T cell acute lymphoblastic leukemia (T-ALL). To pinpoint relevant target genes, we applied a machine learning approach to eliminate genes that were subject to redundant miRNA-mediated control and to identify those genes that were exclusively targeted by tumor-suppressive miRNAs. This strategy revealed the convergence of a small group of tumor suppressor miRNAs on the Myb oncogene, as well as their effects on HBP1, which encodes a transcription factor. The expression of both genes was increased in T-ALL patient samples, and each gene promoted the progression of T-ALL in mice. Hence, our systematic analysis of tumor suppressor miRNA action identified a widespread mechanism of oncogene activation in T-ALL.

AMPK Is Essential to Balance Glycolysis and Mitochondrial Metabolism to Control T-ALL Cell Stress and Survival

“…Importantly, lower T-ALL numbers correlated with increased animal survival (Figure 7E). Consistent with this role for AMPK to support T-ALL, analysis of two published data sets (Homminga et al, 2011; Sanghvi et al, 2014) indicated no loss of expression of AMPKα1 in human T-ALL compared with control cells (Figure S7D). Therefore, despite actively suppressing T-ALL anabolic metabolism, AMPK is essential for T-ALL cell survival and disease progression.…”

MiR-146b negatively regulates migration and delays progression of T-cell acute lymphoblastic leukemia

“…In the present study, we demonstrated that miR-146b-5p downmodulates motility, migration and invasion of T-ALL cells in vitro and leukemia dissemination and disease progression in vivo . Loss of miR-146a (which differs from miR-146b-5p by two nucleotides) in fetal liver hematopoietic progenitors overexpressing activated Notch does not appear to impact tumor onset in a mouse model of Notch-induced T-ALL16. Consequently, miR-146a/b have been discarded from a list of candidate tumor suppressor microRNAs in T-ALL.…”

Pediatric T‐cell acute lymphoblastic leukemia

“…Thus, not only deletions, inactivating mutations, and DNA hypermethylation but also microRNAs target tumor suppressor genes in T‐ALL. Conversely, some miRNAs, for example, miR223, are regulated by T‐ALL oncogenes, such as NOTCH1 and TAL1 (Mansour et al, ; Kumar et al, ), and inactivation of tumor suppressor miRNAs, such as miR29, miR31, miR155, miR193‐3p, and miR200, promotes leukemogenesis by activating the oncogenes HBPI , MCL1 , and MYB (Sanghvi et al, ; Mets et al, ). Other types of noncoding RNA, such as long noncoding RNAs (lncRNAs), have also been implicated in T‐ALL (Wallaert et al, ).…”