Universität zu Köln

Hansen, Julia ORCID: 0000-0001-7828-1269 (2024). Autochthonous Mouse Models as Tools to Study Diffuse Large B-Cell Lymphoma. PhD thesis, Universität zu Köln.

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Abstract

Diffuse Large B-cell Lymphoma (DLBCL) is the most commonly diagnosed lymphoma. The DLBCL subtype C5/MCD recurrently features concurrent mutations of MYD88 and CD79B, overexpression of BCL2, and a plasma cell differentiation block. C5/MCD patients respond particularly poorly to standard first-line chemo-immunotherapy or experience early relapse. This highlights an urgent need for novel therapeutic strategies. In this thesis, an optimized autochthonous mouse model of C5/MCD DLBCL, the PPMBC mouse model, was established. PPMBC mice developed (oligo-)clonal DLBCLs with additional genetic alterations often found in the C5/MCD subtype. These lesions expressed cell surface markers typical for DLBCL and metastasized to extranodal regions. This model enabled the evaluation of treatment strategies, disentangling the effects of a common pro-oncogenic mutation, and exploring metabolic properties. Specifically, we identified a Cd79b ITAM mutation recurrent in C5/MCD DLBCL to confer a targetable tumor reliance on B-cell receptor (BCR) signaling. This CD79BY196X mutation may identify a patient subgroup benefitting of treatment with ibrutinib, an inhibitor for the BCR signaling adaptor BTK, either as a single agent or in combination with other treatments. Furthermore, we determined metabolic alterations accompanying the Cd79b ITAM mutation and ibrutinib treatment in our mouse models. Combining ibrutinib with IACS-010759, an inhibitor of oxidative phosphorylation, demonstrated synergistic viability reduction of murine DLBCL cell lines. Taken together, this work highlights the PPMBC model as a powerful preclinical tool for investigation of targetable C5/MCD DLBCL vulnerabilities and for testing of novel therapy options.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Hansen, Julia julia@ralfmartinhansen.de https://orcid.org/0000-0001-7828-1269 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-740922
Date:	2024
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Außeruniversitäre Forschungseinrichtungen > MPI for Biology of Ageing
Subjects:	Life sciences
Uncontrolled Keywords:	Keywords Language Lymphoma UNSPECIFIED Cancer UNSPECIFIED Mouse Model UNSPECIFIED
Date of oral exam:	2 September 2024
Referee:	Name Academic Title Kashkar, Hamid Prof. Dr. Gehring, Niels Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/74092