ERG and c-MYC regulate a critical gene network in BCR::ABL1-driven B cell acute lymphoblastic leukemia
Details
Publication Year 2024-03-08,Volume 10,Issue #10,Page eadj8803
Journal Title
Science Advances
Publication Type
Research article
Abstract
Philadelphia chromosome-positive B cell acute lymphoblastic leukemia (B-ALL), characterized by the BCR::ABL1 fusion gene, remains a poor prognosis cancer needing new therapeutic approaches. Transcriptomic profiling identified up-regulation of oncogenic transcription factors ERG and c-MYC in BCR::ABL1 B-ALL with ERG and c-MYC required for BCR::ABL1 B-ALL in murine and human models. Profiling of ERG- and c-MYC-dependent gene expression and analysis of ChIP-seq data established ERG and c-MYC coordinate a regulatory network in BCR::ABL1 B-ALL that controls expression of genes involved in several biological processes. Prominent was control of ribosome biogenesis, including expression of RNA polymerase I (POL I) subunits, the importance of which was validated by inhibition of BCR::ABL1 cells by POL I inhibitors, including CX-5461, that prevents promoter recruitment and transcription initiation by POL I. Our results reveal an essential ERG- and c-MYC-dependent transcriptional network involved in regulation of metabolic and ribosome biogenesis pathways in BCR::ABL1 B-ALL, from which previously unidentified vulnerabilities and therapeutic targets may emerge.
Publisher
American Association for the Advancement of Science
Keywords
Animals; Humans; Mice; *Fusion Proteins, bcr-abl/genetics/metabolism/therapeutic use; Gene Regulatory Networks; *Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics/metabolism; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transcription Factors/genetics; *Transcriptional Regulator ERG/genetics
Department(s)
Laboratory Research
Open Access at Publisher's Site
https://doi.org/10.1126/sciadv.adj8803
Terms of Use/Rights Notice
Refer to copyright notice on published article.


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