MCL-1, BCL-xL and Casp-3 as key regulators in thymus homeostasis and thymic epithelial tumors

Müller, Denise

dc.contributor.advisor	Dobbelstein, Matthias Prof. Dr.
dc.contributor.author	Müller, Denise
dc.date.accessioned	2021-12-23T11:25:31Z
dc.date.issued	2021-12-23
dc.identifier.uri	http://hdl.handle.net/21.11130/00-1735-0000-0008-59D1-8
dc.identifier.uri	http://dx.doi.org/10.53846/goediss-9008
dc.language.iso	eng	de
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc	610
dc.title	MCL-1, BCL-xL and Casp-3 as key regulators in thymus homeostasis and thymic epithelial tumors	de
dc.type	cumulativeThesis	de
dc.contributor.referee	Dobbelstein, Matthias Prof. Dr.
dc.date.examination	2021-12-14
dc.description.abstracteng	As a primary lymphatic organ, the thymus is responsible for T cell development and the establishment of the adaptive immune system. The homeostasis and proper function of the thymus epithelium require the strict regulation of apoptosis. While self-reactive T cells are eliminated by apoptotic cell death, the maintenance of the thymus epithelium relies on the upregulation of anti-apoptotic factors. Deficiencies in the apoptotic pathway have been associated with thymic immune disorders and an increased risk for cancer development. Recently, the differential regulation of anti-apoptotic factors has been identified to be characteristic for thymic epithelial tumors (TET), and aggressive tumors have been associated with the overexpression of anti-apoptotic BCL-2 family proteins. Overall, the biology of TET is still poorly understood, and the rarity and heterogeneity of thymic malignancies hamper the identification of common oncogenic drivers and key factors in the pathogenesis of thymic tumors. This is reflected by unsatisfactory personalized treatment strategies, frequent relapses and disease progression. Inhibitory compounds against anti-apoptotic proteins of the BCL-2 family, the BH3 mimetics, are promising new treatment options for apoptotic primed cancerous diseases. Upfront BH3 profiling could help to select patients benefiting most from tailor-made therapies. In this thesis, the clinical relevance of the anti-apoptotic BCL-2 family members MCL-1 and BCL-xL as prognostic markers and potential therapeutic targets in TET has been investigated. We show that a combined inhibition of MCL-1 and BCL-xL eradicates the thymic carcinoma cell line 1889c at very low drug concentrations. Ex vivo functional analyses of primary patient tissue showed specific apoptotic priming of tumor cells, indicating the feasibility of a personalized treatment approach using clinically tested MCL-1 and BCL-xL inhibitors. In a second part, we analyzed the discovery of a 47bp deletion in the CASP3 gene, enriched in TET and in the ageing thymus. This deletion was recurrent and highly frequent and associated with the loss of Casp-3 expression. The accumulation of this deletion in the ageing thymus indicates that the deregulation of apoptosis could contribute to physiological thymus involution, but also the development of thymic diseases.	de
dc.contributor.coReferee	Burfeind, Peter Prof. Dr.
dc.contributor.thirdReferee	Papantonis, Argyris Prof. Dr.
dc.contributor.thirdReferee	Hahn, Heidi Prof. Dr.
dc.contributor.thirdReferee	Heßmann, Elisabeth Pd Dr.
dc.contributor.thirdReferee	Oppermann, Martin Prof. Dr.
dc.subject.ger	thymus	de
dc.subject.ger	thymic epithelial tumors	de
dc.subject.ger	MCL-1	de
dc.subject.ger	BCL-xL	de
dc.subject.ger	Casp-3	de
dc.subject.ger	BH3 mimetics	de
dc.subject.ger	BH3 profiling	de
dc.subject.ger	thymoma	de
dc.subject.ger	thymic carcinoma	de
dc.subject.ger	carcinogenesis	de
dc.subject.ger	thymus involution	de
dc.subject.eng	thymus	de
dc.subject.eng	thymic epithelial tumors	de
dc.subject.eng	MCL-1	de
dc.subject.eng	BCL-xL	de
dc.subject.eng	Casp-3	de
dc.subject.eng	BH3 mimetics	de
dc.subject.eng	BH3 profiling	de
dc.subject.eng	thymoma	de
dc.subject.eng	thymic carcinoma	de
dc.subject.eng	carcinogenesis	de
dc.subject.eng	thymus involution	de
dc.identifier.urn	urn:nbn:de:gbv:7-21.11130/00-1735-0000-0008-59D1-8-6
dc.date.embargoed	2023-12-13
dc.affiliation.institute	Medizinische Fakultät
dc.subject.gokfull	Molekulare Medizin	de
dc.subject.gokfull	Molekularbiologie {Medizin} (PPN619875186)	de
dc.description.embargoed	2023-12-13
dc.identifier.ppn	1783650761

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