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Lookup NU author(s): Patricia Garrido Castro, Professor Olaf Heidenreich
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© 2018 Macmillan Publishers Limited, part of Springer Nature. MLL-rearranged acute lymphoblastic leukaemia (ALL) represents an aggressive malignancy in infants (<1 year of age), associated with poor outcome. Current treatment intensification is not further possible, and novel therapy strategies are needed. Notably, MLL-rearranged ALL is characterised by a strongly deregulated epigenome and shows sensitivity to epigenetic perturbators. Here we demonstrate the in vivo efficacy of the histone deacetylase inhibitor panobinostat (LBH589) using xenograft mouse models of MLL-rearranged ALL. Panobinostat monotherapy showed strong anti-leukaemic effects, extending survival and reducing overall disease burden. Comprehensive molecular analyses in vitro showed that this anti-leukaemic activity involves depletion of H2B ubiquitination via suppression of the RNF20/RNF40/WAC E3 ligase complex; a pivotal pathway for MLL-rearranged leukaemic maintenance. Knockdown of WAC phenocopied loss of H2B ubiquitination and concomitant cell death induction. These combined data demonstrate that panobinostat cross-inhibits multiple epigenetic pathways, ultimately contributing to its highly efficacious targeting of MLL-rearranged ALL.
Author(s): Garrido Castro P, van Roon EHJ, Pinhancos SS, Trentin L, Schneider P, Kerstjens M, te Kronnie G, Heidenreich O, Pieters R, Stam RW
Publication type: Article
Publication status: Published
Journal: Leukemia
Year: 2018
Volume: 32
Issue: 2
Pages: 323-331
Online publication date: 10/07/2017
Acceptance date: 26/06/2017
ISSN (print): 0887-6924
ISSN (electronic): 1476-5551
Publisher: Nature Publishing Group
URL: https://doi.org/10.1038/leu.2017.216
DOI: 10.1038/leu.2017.216
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