Modelling the effect of loss of function CREBBP mutations in the evolution and treatment of B cell acute lymphoblastic leukaemia (B-ALL)

Despite exceptional advances in comprehending B cell acute lymphoblastic leukaemia (B-ALL) pathogenesis and the use of novel treatments, there are still some subtypes classified as high-risk patients and many other who relapse. In this thesis I seek to understand the role of CREBBP mutations in the context of B-ALL. These mutations are conserved among different subtypes of B-ALL including hypodiploid (which have a poor prognosis) and have been found in diagnosis and relapse clones. CREBBP mutations tends to coassociate with RAS pathway mutations in patients. The approach to study CREBBP mutations' role in leukaemogenesis is to model B-ALL by generating Crebbp and/or KRas mutations in mice. I generated a novel Crebbp LOF mutated long latency, intermediate penetrance B-ALL model and identified a potential preleukaemic Lin- IL7R+ ELP population. The interplay between Crebbp KD and KRas mutation was studied in vitro concluding a signalling buffering effect after loss of Crebbp hypothesised to promote cell survival by limiting lethal overactivation in B cells. A new potential use of Venetoclax in CREBBP mutated B-ALL cell lines or in combination with CREBBP inhibitors (Inobrodib) was discovered widening the use of Venetoclax to B-ALL. The hypothesised mechanism relies on the intrinsic ferroptosis sensitivity of CREBBP mutated cell lines to ferroptotic programmed cell death. Due to this, a Venetoclax resistance could be overcome by ferroptotic inducers such as Erastin.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2024

Author dc:creator

• Garcia Gimenez, Alicia

Advisors dc:contributor.advisor

• Richardson, Simon
• Huntly, Brian

• Leukaemia
• B cells
• B-ALL
• CREBBP
• Ferroptosis
• Venetoclax

Licence

• https://www.repository.cam.ac.uk/bitstreams/f4fedf0b-1ab8-4501-81dc-48107390dab0/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.113794

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/376632