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Leukemia. 2019 May 28. doi: 10.1038/s41375-019-0495-8. [Epub ahead of print]

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

Author information

1
Cancer Section, Developmental Biology and Cancer Programme, London, UK.
2
UCL Genomics, UCL GOS Institute of Child Health, London, UK.
3
Department of Haematology, UCL Cancer Institute, London, UK.
4
Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands.
5
Cancer Section, Developmental Biology and Cancer Programme, London, UK. owen.williams@ucl.ac.uk.

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.

PMID:
31138842
DOI:
10.1038/s41375-019-0495-8

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