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

Armenteros-Monterroso, E; Zhao, L; Gasparoli, L; Brooks, T; Pearce, K; Mansour, MR; Martens, JHA; ... Williams, O; + view all (2019) The AAA+ATPase RUVBL2 is essential for the oncogenic function of c-MYB in acute myeloid leukemia. Leukemia 10.1038/s41375-019-0495-8. (In press). Green open access

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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.

Type: Article
Title: The AAA+ATPase RUVBL2 is essential for the oncogenic function of c-MYB in acute myeloid leukemia
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41375-019-0495-8
Publisher version: https://doi.org/10.1038/s41375-019-0495-8
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Preclinical research, Targeted therapies
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health > ICH Development Bio and Cancer Prog
URI: https://discovery.ucl.ac.uk/id/eprint/10075808
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