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

P. Garrido Castro; E. H.J. Van Roon; S. S. Pinhanços; L. Trentin; P. Schneider; M. Kerstjens; G. Te Kronnie; O. Heidenreich; R. Pieters; R. W. Stam

doi:10.1038/leu.2017.216

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

P. Garrido Castro, E. H.J. Van Roon, S. S. Pinhanços, L. Trentin, P. Schneider, M. Kerstjens, G. Te Kronnie, O. Heidenreich, R. Pieters, R. W. Stam

Research output: Contribution to journal › Article › peer-review

48 Citations (Scopus)

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.

Original language	English
Pages (from-to)	323-331
Number of pages	9
Journal	Leukemia
Volume	32
Issue number	2
DOIs	https://doi.org/10.1038/leu.2017.216
Publication status	Published - 1 Feb 2018

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Garrido Castro, P., Van Roon, E. H. J., Pinhanços, S. S., Trentin, L., Schneider, P., Kerstjens, M., Te Kronnie, G., Heidenreich, O., Pieters, R., & Stam, R. W. (2018). 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. Leukemia, 32(2), 323-331. https://doi.org/10.1038/leu.2017.216

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title = "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",

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.",

author = "{Garrido Castro}, P. and {Van Roon}, {E. H.J.} and Pinhan{\c c}os, {S. S.} and L. Trentin and P. Schneider and M. Kerstjens and {Te Kronnie}, G. and O. Heidenreich and R. Pieters and Stam, {R. W.}",

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year = "2018",

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day = "1",

doi = "10.1038/leu.2017.216",

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Garrido Castro, P, Van Roon, EHJ, Pinhanços, SS, Trentin, L, Schneider, P, Kerstjens, M, Te Kronnie, G, Heidenreich, O , Pieters, R & Stam, RW 2018, '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', Leukemia, vol. 32, no. 2, pp. 323-331. https://doi.org/10.1038/leu.2017.216

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. / Garrido Castro, P.; Van Roon, E. H.J.; Pinhanços, S. S. et al.
In: Leukemia, Vol. 32, No. 2, 01.02.2018, p. 323-331.

Research output: Contribution to journal › Article › peer-review

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AU - Pinhanços, S. S.

AU - Trentin, L.

AU - Schneider, P.

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AU - Te Kronnie, G.

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AU - Pieters, R.

AU - Stam, R. W.

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SN - 0887-6924

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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

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