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Acute myeloid leukemia

The AAA+ATPase RUVBL2 is essential for the oncogenic function of c-MYB in acute myeloid leukemia

Leukemia volume 33, pages 2817–2829 (2019)Cite this article

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Abstract

Subtype-specific leukemia oncogenes drive aberrant gene expression profiles that converge on common essential mediators to ensure leukemia self-renewal and inhibition of differentiation. The transcription factor c-MYB functions as one such mediator in a diverse range of leukemias. Here we show for the first time that transcriptional repression of myeloid differentiation associated c-MYB target genes in AML is enforced by the AAA+ ATPase RUVBL2. Silencing RUVBL2 expression resulted in increased binding of c-MYB to these loci and their transcriptional activation. RUVBL2 inhibition resulted in AML cell apoptosis and severely impaired disease progression of established AML in engrafted mice. In contrast, such inhibition had little impact on normal hematopoietic progenitor differentiation. These data demonstrate that RUVBL2 is essential for the oncogenic function of c-MYB in AML by governing inhibition of myeloid differentiation. They also indicate that targeting the control of c-MYB function by RUVBL2 is a promising approach to developing future anti-AML therapies.

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Acknowledgements

The authors thank Ayad Eddaoudi and Stephanie Canning, UCL GOS ICH Flow Cytometry Facility, for providing assistance with flow cytometry, all the staff of the UCL GOS ICH Western Laboratories for excellent animal husbandry. EAM was supported by a PhD studentship from Bloodwise (12068), LZ by a PhD studentship from the Medical Research Council (MRC DTG), and LG by a project grant from Children with Cancer UK (14-169). MRM was supported by a Bennett Fellowship from Bloodwise and National Institute for Health Research University College London BRC Senior Clinical Research Fellowship, and JdB by a fellowship from the Alternative Hair Charitable Foundation and Great Ormond Street Hospital Children’s Charity. Research in the laboratory of JHAM was supported by KIKA, and OW (V1305, V2617) was supported by grants from the Great Ormond Street Hospital Children’s Charity. This research was supported by the NIHR Great Ormond Street Hospital Biomedical Research Center.

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Authors and Affiliations

  1. Cancer Section, Developmental Biology and Cancer Programme, London, UK

    Elena Armenteros-Monterroso, Lu Zhao, Luca Gasparoli, Jasper de Boer & Owen Williams

  2. UCL Genomics, UCL GOS Institute of Child Health, London, UK

    Tony Brooks & Kerra Pearce

  3. Department of Haematology, UCL Cancer Institute, London, UK

    Marc R. Mansour

  4. Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands

    Joost H. A. Martens

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  1. Elena Armenteros-Monterroso
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EAM, LZ, LG, and OW performed the experiments and data analysis. TB and KP performed the RNA-sequencing and ChIP-sequencing experiments, and JHAM analysed ChIP-sequencing data. OW, JdB, and MRM provided project leadership and supervised the research. EAM and OW wrote the paper. All authors read, provided critical comments and approved the manuscript.

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Correspondence to Owen Williams.

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Armenteros-Monterroso, E., Zhao, L., Gasparoli, L. et al. The AAA+ATPase RUVBL2 is essential for the oncogenic function of c-MYB in acute myeloid leukemia. Leukemia 33, 2817–2829 (2019). https://doi.org/10.1038/s41375-019-0495-8

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