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.

Semaphorin‐3A (Sema3A) and vascular endothelial growth factor (VEGF165) are ligands of neuropilin‐1 (NRP‐1 or CD304) and are related to immunoregulation and tumor angiogenesis, respectively. However, possible interactions between NRP‐1 and Sema3A and VEGF165 in acute leukemia remain unclear, especially whether Sema3A plays a role in acute leukemia. In this study, both of the proportion of regulatory T cells (Tregs) and their expression of NRP‐1 were found to increase in acute leukemia patients compared with healthy controls. In contrast, lower mRNA and plasma levels of Sema3A were detected in the acute leukemia patients. In vitro, the addition of exogenous Sema3A inhibited the expression of NRP‐1 on Tregs and it promoted apoptosis of leukemia cells. However, in the presence of anti‐Sema3A antibody, the effect of rhSema3A on NRP‐1 expression was reversed. These results suggest that Sema3A promotes apoptosis in leukemia cells by inhibiting expression of NRP‐1, and thus, represents a tumor suppressor protein with a role in the pathogenesis of acute leukemia. Consequently, NRP‐1/Sema3A signaling may represent a novel target for the treatment of acute leukemia and should be further studied. Anat Rec, 302:1127–1135, 2019. © 2018 Wiley Periodicals, Inc.

N6-methyladenosine (m6A), the most abundant modification in mRNAs, has been defined as a crucial modulator in the progression of acute myeloid leukemia (AML). Identification of the key regulators of m6A modifications in AML could provide further insights into AML biology and uncover more effective therapeutic strategies for AML patients. Here we report overexpression of YTHDF1, an m6A reader protein, in human AML samples at the protein level with enrichment in leukemia stem cells (LSCs). Whereas YTHDF1 was dispensable for normal hematopoiesis in mice, depletion of YTHDF1 attenuated self-renewal, proliferation, and leukemic capacity of primary human and mouse AML cells in vitro and in vivo. Mechanistically, YTHDF1 promoted the translation of cyclin E2 in an m6A-dependent manner. Structure-based virtual screening of FDA-approved drugs identified tegaserod as a potential YTHDF1 inhibitor. Tegaserod blocked the direct binding of YTHDF1 with m6A-modified mRNAs and inhibited YTHDF1-regulated cyclin E2 translation. Moreover, tegaserod reduced the viability of patient-derived AML cells in vitro and prolonged survival in patient-derived xenograft models. Together, our study defines YTHDF1 as an integral regulator of AML progression by regulating the expression of m6A-modified mRNAs, which might serve as a potential therapeutic target for AML.