Investigating the role of BTKi and the histone variant macroH2A1 in chronic lymphocytic leukaemia

Abstract

Chronic Lymphocytic Leukaemia (CLL) is a highly heterogeneous CD5+ lymphoproliferative disorder. Epigenetic phenomena play an important role in CLL. Bruton’s tyrosine kinase (BTK), part of the B cell receptor signalling, has been targeted therapeutically and has led to a paradigm shift in CLL treatment. BTK inhibition by Ibrutinib has been associated with changes at the epigenetic level and shown to alter the CLL enhancer landscape.

A MACROH2A1-related Ibrutinib-responsive active region was discovered in matched pre-/post-Ibrutinib treated CLL samples by H3K27ac ChIP-seq. MacroH2A1 is a histone variant with an important role in genome stability. Additionally, integrated analysis of this ChIP-seq with RNA-seq data from the matched pre-/post-Ibrutinib treated CLL patient samples revealed several genes shown to be altered upon Ibrutinib. Together, patient and cell lines data suggest Ibrutinib may have an impact on macroH2A1 and its isoforms in CLL as well as other genes.

This work provides first evidence for a role of macroH2A1 and its epigenetic regulation in CLL in the context of BTK inhibitor treatment. The multifaceted role of macroH2A1 in disease, its potential as a therapeutic target and the knowledge gap in the CLL/BTK context, suggest that dissection of macroH2A1’s role on the epigenetic axis demands further investigation.

Thesis is embargoed until 31 July 2029.

Date of Award	Jul 2024
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Northern Ireland Department for the Economy, Leukaemia & Lymphoma NI & Federation of European Biochemical Societies
Supervisor	Effie Kostareli (Supervisor) & Ken Mills (Supervisor)