ERG and c-MYC regulate a critical gene network in BCR::ABL1-driven B cell acute lymphoblastic leukemia

Behrens, K; Brajanovski, N; Xu, Z; Viney, EM; DiRago, L; Hediyeh-Zadeh, S; Davis, MJ; Pearson, RB; Sanij, E; Alexander, WS; Ng, AP

Author(s): Behrens, K; Brajanovski, N; Xu, Z; Viney, EM; DiRago, L; Hediyeh-Zadeh, S; Davis, MJ; Pearson, RB; Sanij, E; Alexander, WS; Ng, AP;
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
Publisher's Version: https://doi.org/10.1126/sciadv.adj8803
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.

Creation Date: 2024-03-28 06:48:08

Last Modified: 2024-03-28 06:51:46