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Leukemia. 2018 Feb;32(2):323-331. doi: 10.1038/leu.2017.216. Epub 2017 Jul 10.

The HDAC inhibitor panobinostat (LBH589) exerts in vivo anti-leukaemic activity against MLL-rearranged acute lymphoblastic leukaemia and involves the RNF20/RNF40/WAC-H2B ubiquitination axis.

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Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.
Department of Pediatric Hematology/Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
Department of Women's and Children's Health, University of Padova, Padova, Italy.
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
North of England Stem Cell Institute, Newcastle and Durham Universities, Newcastle upon Tyne, UK.


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.

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