Eya2 is critical for the E2A‑HLF‑mediated immortalization of mouse hematopoietic stem/progenitor cells

Abstract

The immunoglobulin enhancer-binding factor/ hepatic leukemia factor (E2A-HLF) oncogenic fusion gene, generated by t(17;19)(q22;p13) translocation in childhood B-cell acute lymphoblastic leukemia with a very poor prognosis, encodes a chimeric transcription factor in which the transactivation domains of E2A are fused to the DNA-binding and dimerization domain of HLF.E2A-HLF has been demonstrated to have an anti-apoptotic effect. However, the molecular mechanism underlying E2A-HLF-mediated leukemogenesis remains unclear. The present study identified EYA transcriptional coactivator and phosphatase 2 (Eya2), the forced expression of which is known to immortalize mouse hematopoietic stem/progenitor cells (HSPCs), as a direct target molecule downstream of E2A-HLF. E2A-HLF-immortalized mouse HSPCs expressed Eya2 at a high level in the aberrant self-renewal program. Chromatin immunoprecipitation-quantitative polymerase chain reaction and a reporter assay revealed that E2A-HLF enhanced the Eya2 expression by binding to the promoter region containing the E2A-HLF-binding consensus sequence. Eya2 knockdown in E2A-HLF-immortalized cells resulted in reduced colony-forming efficiency. These results suggest a critical role of Eya2 in E2A-HLF-mediated leukemogenesis.

A Comprehensive Analysis of Metabolomics and Transcriptomics Reveals Novel Biomarkers and Mechanistic Insights on Lorlatinib Crosses the Blood-Brain Barrier

“…The complex network contained five genes, which were CYP4B1, GALNT3, DAO, NDST4, EYA2, and 13 metabolites, which were Sphingomyelin, Dihydroceramide, Sphingosine, Thiamin diphosphate, 1-Acyl-sn-glycero-3-phosphocholine, Phosphatidylcholine, Choline, Phosphatidate, Phosphatidylserine, Phosphatidylethanolamine, L-Cysteine, beta-D-Galactosyl-1,4-beta-D-Glucosylceramide and Sulfatide. Related genes encode enzymes belonging to different superfamilies, catalyzing many reactions involved in: metabolism of certain xenobiotics ( Lim et al, 2020 ; Baer and Rettie, 2006 ), posttranslational modification of protein ( Takashi and Fukumoto, 2020 ), N-methyl-d-aspartate receptor regulation, glutamate metabolism ( Yang et al, 2013 ), modification in the heparan sulfate biosynthetic pathway ( Li et al, 2018 ) and transcriptional activation ( Devi Maharjan et al, 2019 ). The results of the presented integrated metabolomics and transcriptomics analysis prove that the pathway is concentrated on Sphingolipid metabolism and Glycerophospholipid metabolism, which is consistent with the enrichment results.…”