MCL-1, BCL-xL and Casp-3 as key regulators in thymus homeostasis and thymic epithelial tumors
by Denise Müller
Date of Examination:2021-12-14
Date of issue:2021-12-23
Advisor:Prof. Dr. Matthias Dobbelstein
Referee:Prof. Dr. Matthias Dobbelstein
Referee:Prof. Dr. Peter Burfeind
Referee:Prof. Dr. Argyris Papantonis
Referee:Prof. Dr. Heidi Hahn
Referee:Dr. Elisabeth Pd Heßmann
Referee:Prof. Dr. Martin Oppermann
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EnglishAs 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.
Keywords: thymus; thymic epithelial tumors; MCL-1; BCL-xL; Casp-3; BH3 mimetics; BH3 profiling; thymoma; thymic carcinoma; carcinogenesis; thymus involution
Schlagwörter: thymus; thymic epithelial tumors; MCL-1; BCL-xL; Casp-3; BH3 mimetics; BH3 profiling; thymoma; thymic carcinoma; carcinogenesis; thymus involution