- Zach A. Dixon1,
- Lindsay Nicholson2,
- Martin Zeppetzauer3,
- Elizabeth Matheson1,
- Paul Sinclair1,
- Christine J. Harrison1 and
- Julie A.E. Irving1,*
- 1 Newcastle Cancer Centre, Newcastle University, Newcastle upon Tyne, UK;
- 2 Academic Haematology, Newcastle University, Newcastle upon Tyne, UK;
- 3 Children Cancer Research Institute (CCRI), Leukemia Biology Group, Vienna, Austria
- ↵* Corresponding author; email:
Relapsed acute lymphoblastic leukaemia is the most common cause of cancer related mortality in young people and new therapeutic strategies are needed to improve outcome. Recent studies have shown that heterozygous inactivating mutations in the histone acetyl transferase, CREBBP, are particularly frequent in relapsed childhood acute lymphoblastic leukaemia and associated with a hyperdiploid karyotype and KRAS mutations. To study the functional impact of CREBBP haploinsufficiency in acute lymphoblastic leukaemia, RNA interference was used to knock down expression of CREBBP in acute lymphoblastic leukaemia cell lines and various primagraft acute lymphoblastic leukaemia cells. We demonstrate that attenuation of CREBBP results in reduced acetylation of histone 3 lysine 18, but had no significant impact on cAMP-dependent target gene expression. Impaired induction of glucocorticoid receptor targets was only seen in 1 of 4 CREBBP knockdown models, and there was no significant difference in glucocorticoid-induced apoptosis, sensitivity to other acute lymphoblastic leukaemia chemotherapeutics or histone deacetylase inhibitors. Importantly, we show that CREBBP directly acetylates KRAS and that CREBBP knockdown enhances signalling of the RAS/RAF/MEK/ERK pathway in Ras pathway mutated acute lymphoblastic leukaemia cells, which are still sensitive to MEK inhibitors. Thus, CREBBP mutations might assist in enhancing oncogenic RAS signalling in acute lymphoblastic leukaemia but do not alter response to MEK inhibitors.
- Received April 15, 2016.
- Accepted December 13, 2016.
- Copyright © 2016, Ferrata Storti Foundation