Universität zu Köln

Breull-Wierschem, Leonie (2024). Identifying mechanisms of resistance to BCL2 inhibitor venetoclax in acute myeloid leukemia (AML). PhD thesis, Universität zu Köln.

PDF BreullWierschemLeonieDissertation.pdf Download (14MB)

Abstract

The BCL2 inhibitor venetoclax (ABT-199) has improved therapeutic options for acute myeloid leukemia (AML) patients ineligible for intensive treatment regimens. However, intrinsic and acquired resistance massively impedes drug efficacy. Here, we aimed to elucidate mechanisms of venetoclax resistance in AML by characterizing a heterogeneous panel of venetoclax-resistant AML cell lines on DNA, RNA, and protein level. For this purpose, we generated AML cell lines with acquired resistance against venetoclax. We then identified driving forces of venetoclax resistance including impaired mitochondrial apoptosis, upregulation of tumor-promoting pathways and mutations of TP53. Single cell RNA sequencing results of AML patient samples pre and post venetoclax resistance emphasized the role of altered mitochondrial homeostasis in the emergence of resistance. Furthermore, we demonstrated that selectively targeting mitochondrial apoptosis, especially via MCL1 inhibition, circumvents venetoclax resistance in AML cell lines. Taken together, these results improve understanding of intrinsic and acquired venetoclax resistance and identify potential therapeutic targets for the treatment of AML patients unfit for intensive therapy.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Breull-Wierschem, Leonie leonie.breull@gmail.com UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-742888
Date:	2024
Language:	English
Faculty:	Faculty of Medicine
Divisions:	Faculty of Medicine > Innere Medizin > Klinik I für Innere Medizin - Hämatologie und Onkologie
Subjects:	Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language acute myeloid leukemia English venetoclax English drug resistance English apoptosis English Bcl2 protein family English AML English BCL2 inhibitor English
Date of oral exam:	26 September 2024
Referee:	Name Academic Title Frenzel, Lukas-Peter Privatdozent Dr. med. Kashkar, Hamid Universitätsprofessor Dr. rer. nat.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/74288