The role of CREBBP mutations in lymphoid malignancies

Abstract

Relapsed acute lymphoblastic leukaemia (ALL), diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) comprise a group of malignancies with poor prognosis and therapeutic strategies are needed to improve outcomes. Recent studies have shown that heterozygous inactivating mutations in the histone acetyl transferase, CREBBP, are frequent in these malignancies, and are thought to lead to impaired transcription of glucocorticoid (GC) response genes. Given the pivotal role of GC in the treatment of lymphoid malignancies and the finding that CREBBP mutations often arise at relapse, it has been postulated that CREBBP mutations confer chemoresistance to GC therapy. To study the role of CREBBP haploinsufficiency in ALL, DLBCL and FL, small hairpin RNA and small interfering RNA methods were used to knock down CREBBP in a number of cell lines and primary derived samples. Models were functionally relevant, with reduced acetylation of CREBBP target residue, histone 3 lysine 18 and/or histone 3 lysine 27, but knockdown had no significant impact on activation of cAMP-dependent target genes. Impaired induction of glucocorticoid receptor targets was only seen in 1 of 4 CREBBP knockdown models of ALL, and there was no significant difference in GC-induced apoptosis or chemosensitivity to other therapeutic agents frequently used in lymphoid malignancies, including histone deacetylase inhibitors. However, CREBBP knockdown was associated with enhanced signalling of the RAS/RAF/MEK/ERK pathway in RAS pathway mutant ALL cells, and MEK inhibitor sensitivity was retained. This suggests that CREBBP mutation may act to enhance the activity of oncogenes and that CREBBP/RAS pathway mutated relapsed ALL are candidates for MEK inhibitor clinical trials.