title: The AAA+ ATPase RUVBL2 is a critical mediator of MLL-AF9 oncogenesis.
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.
authors: Molecular Haematology and Cancer Biology Unit, UCL Institute of Child Health, London, UK.
authors: H
authors: H
authors: Osaki
authors: V
authors: V
authors: Walf-Vorderwülbecke
authors: M
authors: M
authors: Mangolini
authors: L
authors: L
authors: Zhao
authors: S J
authors: SJ
authors: Horton
authors: G
authors: G
authors: Morrone
authors: J J
authors: JJ
authors: Schuringa
authors: J
authors: J
authors: de Boer
authors: O
authors: O
authors: Williams
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic / Q000502:physiology; D006801:Humans; D015456:Leukemia, Biphenotypic, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D019098:Telomerase / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C474558:MLL-AF9 fusion protein, human; C551356:MLL-AF9 fusion protein, mouse; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein; D019098:Telomerase; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities; D004265:DNA Helicases; C122079:RUVBL2 protein, human; C518330:RUVBL2 protein, mouse