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 þ 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.

The plant Pontin and Reptin homologues, RuvBL1 and RuvBL2a, colocalize with TERT and TRB proteins in vivo, and participate in telomerase biogenesis

“…RuvBL proteins belong to the evolutionarily highly conserved AAA+ family (ATPase Associated with various cellular Activities) that are involved in ATP binding and hydrolysis (Matias et al ., ). Eukaryotic RuvBL1 (Pontin, TIP49a, Rvb1, TAP54α) and RuvBL2 (Reptin, TIP48, TIP49b, Rvb2, TAP54β) participate in many diverse cellular activities like chromatin remodeling (Jha et al ., ), transcriptional regulation (Ohdate et al ., ; Gallant, ), oncogenic transformation (Osaki et al ., ), epigenetic regulations (Gallant, ) or DNA‐damage signaling (Rosenbaum et al ., ). RuvBL1 and RuvBL2 can also play a role in the assembly of box C/D or H/ACA of small nucleolar RNAs (snoRNAs) with specific proteins to form functional ribonucleoprotein particles (RNPs) (Watkins et al ., ; McKeegan et al ., ; Boulon et al ., ; Zhao et al ., ).…”

Targeting acute myeloid leukemia by drug-induced c-MYB degradation

“…However, progress has not been uniform across all subtypes of disease and many pediatric 1 and adult 2 Acute Myeloid Leukemia (AML) patients cannot be cured by current therapies. It is widely accepted that further intensification of chemotherapy is unlikely to improve outcomes, 3,4 but that this may be achieved by developing novel therapeutics targeting specific leukemia drug-susceptibilities.…”

Control of Lineage Commitment in Acute Leukaemia

“…Models of MLLr leukaemia Several MLLr models have been developed to understand the oncogenic mechanisms of the rearrangement. The MLL/AF9 fusion gene has been demonstrated to induce ALL or AML in vitro and in vivo in mice [74,75]. It has been shown that microenvironmental factors impact on lineage commitments of MLL/AF9 acute leukaemia, i.e.…”