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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

Lookup NU author(s): Patricia Garrido Castro, Professor Olaf Heidenreich

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Abstract

© 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.

Publication metadata

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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