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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.

Author information

1
Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.
2
Department of Pediatric Hematology/Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
3
Department of Women's and Children's Health, University of Padova, Padova, Italy.
4
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
5
North of England Stem Cell Institute, Newcastle and Durham Universities, Newcastle upon Tyne, UK.

Abstract

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.

PMID:
28690313
DOI:
10.1038/leu.2017.216
[Indexed for MEDLINE]

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