1. ERG and c-MYC regulate a critical gene network in BCR::ABL1-driven B cell acute lymphoblastic leukemia
- Author
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Behrens, K, Brajanovski, N, Xu, Z, Viney, EM, Dirago, L, Hediyeh-Zadeh, S, Davis, MJ, Pearson, RB, Sanij, E, Alexander, WS, Ng, AP, Behrens, K, Brajanovski, N, Xu, Z, Viney, EM, Dirago, L, Hediyeh-Zadeh, S, Davis, MJ, Pearson, RB, Sanij, E, Alexander, WS, and Ng, AP
- 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.
- Published
- 2024