Journal
BRITISH JOURNAL OF HAEMATOLOGY
Volume 182, Issue 4, Pages 542-553Publisher
WILEY
DOI: 10.1111/bjh.15436
Keywords
paediatric acute leukaemia; KMT2A (MLL); histone deacetylases; HDAC inhibitors; epigenetics
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Funding
- Obra Social from Hospital Sant Joan de Deu project
- Forca Miquel project
- Asociacion Pulseras Candela project
- Pirata Barballum project
- Magic project
- Mua project
- Plan Nacional de I+D+I [PI12/02417, PI16/00246]
- ISCIII - Subdireccion General de Evaluacion y Fomento de la Investigacion Sanitaria
- Fondo Europeo de Desarrollo Regional (FEDER)
- CIBERER
- Fundacion AECC-Cancer Infantil 2012
- Fundacion Cris contra el cancer
- Fundacion Pelayo
- Fundacion Unoentrecienmil
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Histone deacetylase inhibitors (HDACi) had emerged as promising drugs in leukaemia, but their toxicity due to lack of specificity limited their use. Therefore, there is a need to elucidate the role of HDACs in specific settings. The study of HDAC expression in childhood leukaemia could help to choose more specific HDACi for selected candidates in a personalized approach. We analysed HDAC1-11, SIRT1, SIRT7, MEF2C and MEF2D mRNA expression in 211 paediatric patients diagnosed with acute leukaemia. There was a global overexpression of HDACs, while specific HDACs correlated with clinical and biological features, and some even predicted outcome. Thus, some HDAC and MEF2C profiles probably reflected the lineage and the maturation of the blasts and some profiles identified specific oncogenic pathways active in the leukaemic cells. Specifically, we identified a distinctive signature for patients with KMT2A (MLL) rearrangement, with high HDAC9 and MEF2D expression, regardless of age, KMT2A partner and lineage. Moreover, we observed an adverse prognostic value of HDAC9 overexpression, regardless of KMT2A rearrangement. Our results provide useful knowledge on the complex picture of HDAC expression in childhood leukaemia and support the directed use of specific HDACi to selected paediatric patients with acute leukaemia.
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