Integrated analysis of microRNA and transcription factor reveals important regulators and regulatory motifs in adult B-cell acute lymphoblastic leukemia

Abstract

B-cell acute lymphoblastic leukemia (B‑ALL) is an aggressive hematological malignancy and a leading cause of cancer-related mortality in children and young adults. The molecular mechanisms involved in the regulation of its gene expression has yet to be fully elucidated. In the present study, we performed large scale expression profiling of microRNA (miRNA) and transcription factor (TF) by Illumina deep‑sequencing and TF array technology, respectively, and identified 291 differentially expressed miRNAs and 201 differentially expressed TFs in adult B‑ALL samples relative to their controls. After integrating expression profile data with computational prediction of miRNA and TF targets from different databases, we construct a comprehensive miRNA‑TF regulatory network specifically for adult B‑ALL. Network function analysis revealed 25 significantly enriched pathways, four pathways are well‑known to be involved in B‑ALL, such as PI3K‑Akt signaling pathway, Jak‑STAT signaling pathway, Ras signaling pathway and cell cycle pathway. By analyzing the network topology, we identified 28 hub miRNAs and 19 hub TFs in the network, and found nine potential B‑ALL regulators among these hub nodes. We also constructed a Jak‑STAT signaling sub‑network for B‑ALL. Based on the sub‑network analysis and literature survey, we proposed a cellular model to discuss MYC/miR‑15a‑5p/FLT3 feed-forward loop (FFL) with Jak‑STAT signaling pathway in B‑ALL. These findings enhance our understanding of this disease at the molecular level, as well as provide putative therapeutic targets for B-ALL.

Integrated analysis of microRNA and transcription factors in the bone marrow of patients with acute monocytic leukemia

“…The remaining reads of ≥15 nucleotides were aligned to a known reference miRNA precursor in the miRBase database (release 19.0; www.mirbase.org/) using Novoalign software (version v2.07.11; www.novocraft.com/). Normalization of read counts, calculation of the relative expression levels of each miRNA and identification of differentially expressed miRNAs were performed as previously described (13).…”

The role of microRNAs in acute lymphoblastic leukaemia: From biology to applications

“…A study by Lin et al identified the relationship between miR‐15a‐5p and FMS‐like tyrosine kinase3 (FLT3). In summary, miR‐15a inhibits FLT3 activity, and MYC suppresses miR‐15a and increases FLT3 activity directly.…”

“…In addition, MYC plays a critical role in regulating STAT5B. Finally, this positive feedback leads to the promotion of cell proliferation in ALL …”

Advances in Acute Myeloid Leukemia Stem Cells

“…In recent years, studies on micro-RNA and transcription factors in leukemia patients have become increasingly mature. For example, the transcription factor MYC can inhibit the expression of the shared target gene FLT3 by miR-15a-5p, and FLT3 plays a crucial role in activating the STAT5A pathway and promoting tumor cell proliferation [92,93], but its specific mechanism of influence on the development of tumor remains to be further investigated. Targeted drugs in mounting numbers for LSCs signaling pathways are being developed, but most of them are still in the stage of animal experiments, and more research is needed to determine the safety and efficacy in humans.…”