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

Abstract

Philadelphia chromosome-positive B cell acute lymphoblastic leukemia (B-ALL), characterized by the <i>BCR::ABL1</i> 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 <i>BCR::ABL1</i> B-ALL with ERG and c-MYC required for <i>BCR::ABL1</i> 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 <i>BCR::ABL1</i> 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 <i>BCR::ABL1</i> 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 <i>BCR::ABL1</i> B-ALL, from which previously unidentified vulnerabilities and therapeutic targets may emerge.