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CREBBP knockdown enhances RAS/RAF/MEK/ERK signaling in Ras pathway mutated acute lymphoblastic leukemia but does not modulate chemotherapeutic response

Lookup NU author(s): Zach Dixon, Dr Lindsay Nicholson, Elizabeth Matheson, Dr Paul Sinclair, Professor Christine Harrison FRCPath FMedSci, Professor Julie Irving

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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).

Abstract

© 2017 Ferrata Storti Foundation. Relapsed acute lymphoblastic leukemia 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 leukemia and associated with a hyperdiploid karyotype and KRAS mutations. To study the functional impact of CREBBP haploinsufficiency in acute lymphoblastic leukemia, RNA interference was used to knock down expression of CREBBP in acute lymphoblastic leukemia cell lines and various primagraft acute lymphoblastic leukemia cells. We demonstrate that attenuation of CREBBP results in reduced acetylation of histone 3 lysine 18, but has 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 leukemia chemother-apeutics or histone deacetylase inhibitors. Importantly, we show that CREBBP directly acetylates KRAS and that CREBBP knockdown enhances signaling of the RAS/RAF/MEK/ERK pathway in Ras pathway mutated acute lymphoblastic leukemia cells, which are still sensitive to MEK inhibitors. Thus, CREBBP mutations might assist in enhancing oncogenic RAS signaling in acute lymphoblastic leukemia but do not alter response to MEK inhibitors.

Publication metadata

Author(s): Dixon ZA, Nicholson L, Zeppetzauer M, Matheson E, Sinclair P, Harrison CJ, Irving JAE

Publication type: Article

Publication status: Published

Journal: Haematologica

Year: 2017

Volume: 102

Issue: 4

Pages: 736-745

Print publication date: 01/04/2017

Online publication date: 15/12/2016

Acceptance date: 13/12/2016

Date deposited: 08/06/2017

ISSN (print): 0390-6078

ISSN (electronic): 1592-8721

Publisher: Ferrata Storti Foundation

URL: https://doi.org/10.3324/haematol.2016.145177

DOI: 10.3324/haematol.2016.145177

PubMed id: 27979926

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