ERG and c-MYC regulate a critical gene network in BCR::ABL1-driven B cell acute lymphoblastic leukemia.
Kira BehrensNatalie BrajanovskiZhen XuElizabeth M VineyLadina DiRagoSoroor Hediyeh-ZadehMelissa J DavisRichard B PearsonElaine SanijWarren S AlexanderAshley P NgPublished in: Science advances (2024)
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.
Keyphrases
- chronic myeloid leukemia
- poor prognosis
- acute lymphoblastic leukemia
- tyrosine kinase
- transcription factor
- gene expression
- single cell
- long non coding rna
- genome wide
- dna methylation
- copy number
- allogeneic hematopoietic stem cell transplantation
- genome wide identification
- induced apoptosis
- high throughput
- squamous cell carcinoma
- machine learning
- dna binding
- binding protein
- mouse model
- artificial intelligence
- cell cycle arrest
- quality control
- induced pluripotent stem cells