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

Author:

Behrens Kira12ORCID,Brajanovski Natalie3ORCID,Xu Zhen12,Viney Elizabeth M.1,DiRago Ladina4ORCID,Hediyeh-Zadeh Soroor25ORCID,Davis Melissa J.25678,Pearson Richard B.391011,Sanij Elaine39101112ORCID,Alexander Warren S.12,Ng Ashley P.24ORCID

Affiliation:

1. Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.

2. Department of Medical Biology, University of Melbourne, Parkville, Australia.

3. Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Australia.

4. Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.

5. Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.

6. Department of Clinical Pathology, University of Melbourne, Parkville, Australia.

7. The Diamantina Institute, The University of Queensland, Woolloongabba, Australia.

8. The South Australian Immunogenomics Cancer Institute, The University of Adelaide, Adelaide, Australia.

9. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia.

10. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia.

11. Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Australia.

12. St. Vincent’s Institute of Medical Research, Fitzroy, Australia.

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 (AAAS)

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