The AAA(+) ATPase RUVBL2 is a critical mediator of MLL-AF9 oncogenesis

H. Osaki, V. Walf-Vorderwuebecke, M. Mangolini, L. Zhao, S. J. Horton, G. Morrone, J. J. Schuringa, J. de Boer, O. Williams*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

24 Citations (Scopus)

Abstract

The most frequent chromosomal translocations in pediatric acute myeloid leukemia affect the 11q23 locus and give rise to mixed lineage leukemia (MLL) fusion genes, MLL-AF9 being the most prevalent. The MLL-AF9 fusion gene has been shown to induce leukemia in both mouse and human models. In this study, we demonstrate that leukemogenic activity of MLL-AF9 requires RUVBL2 (RuvB-like 2), an AAA+ ATPase family member that functions in a wide range of cellular processes, including chromatin remodeling and transcriptional regulation. Expression of RUVBL2 was dependent on MLL-AF9, as it increased upon immortalization of human cord blood-derived hematopoietic progenitor cells with the fusion gene and decreased following loss of fusion gene expression in conditionally immortalized mouse cells. Short hairpin RNA-mediated silencing experiments demonstrated that both the immortalized human cells and the MLL-AF9-expressing human leukemia cell line THP-1 required RUVBL2 expression for proliferation and survival. Furthermore, inhibition of RUVBL2 expression in THP-1 cells led to reduced telomerase activity and clonogenic potential. These data were confirmed with a dominant-negative Walker B-mutated RUVBL2 construct. Taken together, these data suggest the possibility of targeting RUVBL2 as a potential therapeutic strategy for MLL-AF9-associated leukemia.

Original languageEnglish
Pages (from-to)1461-1468
Number of pages8
JournalLeukemia
Volume27
Issue number7
DOIs
Publication statusPublished - Jul-2013

Keywords

  • AML
  • MLL-AF9
  • apoptosis
  • telomerase
  • LEUKEMIA STEM-CELLS
  • HUMAN HEPATOCELLULAR-CARCINOMA
  • ACUTE MYELOID-LEUKEMIA
  • MLL-ENL
  • FUSION PROTEINS
  • C-MYC
  • HEMATOPOIETIC-CELLS
  • GENE-EXPRESSION
  • SELF-RENEWAL
  • TELOMERASE

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