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

American Association for the Advancement of Science 2024-03-08

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.

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https://creativecommons.org/licenses/cc-by-nc/4.0

UMV oai:jupiter.its.unimelb.edu.au:11343/345538
Behrens, K., Brajanovski, N., Xu, Z., Viney, E. M., Dirago, L., Hediyeh-Zadeh, S., Davis, M. J., Pearson, R. B., Sanij, E., Alexander, W. S. & Ng, A. P. (2024). ERG and c-MYC regulate a critical gene network in BCR::ABL1-driven B cell acute lymphoblastic leukemia. Science Advances, 10 (10), https://doi.org/10.1126/sciadv.adj8803.
10.1126/sciadv.adj8803
2375-2548
2375-2548
1456029907

UNIV OF MELBOURNE
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