Vergleichende immunhistochemische Analyse onkogener Signalwegssignaturen in Lymphomen

by Philipp Vincent Stauder
Doctoral thesis
Date of Examination:2023-03-07
Date of issue:2023-03-03
Advisor:Prof. Dr. Philipp Ströbel
Referee:Prof. Dr. Gerald Wulf
Referee:Prof. Dr. Ralf Dressel
Persistent Address: http://dx.doi.org/10.53846/goediss-9752

 

 

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Abstract

English

B-cell lymphomas are a group of malign neoplasms derived from lymphoid B-cells. The targeted therapy of B-cell lymphomas includes the inhibition of oncogene signaling which is mediated via the B-cell receptor (BCR). However, for the treatment of the highly aggressive Burkitt lymphoma (BL) there is still a lack of such therapies. The aim of this study was to identify new possible targets of chronic BCR-signaling in BL and examine the protein expression in tissue samples of different B-cell lymphomas in a comparative analysis. Based on the re-evaluation of published data from an RNA-mediated interference screen and phosphoproteomic analyses on BL cells lines in vitro, the proteins ACTN4, ARFGEF2, BCL11A, CARD11, CDKN1B and MTHFD1 as well as the MTHFD1-related proteins MTHFD2 and SHMT2 were selected for a protein expression analysis. This was carried out by immunohistochemistry staining of human tissue samples of BL, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, B-cell chronic lymphatic leukemia, multiple myeloma and Hodgkin lymphoma. Moreover, survival time analyses were conducted to examine the prognostic value of protein expression in lymphoma patients. The study revealed that apart from CDKN1B all the proteins are highly expressed in BL, but that the expression is not specific for this entity. Interestingly ACTN4, whose role in the context of lymphoid neoplasms and BCR-signaling has been unknown so far, showed high protein levels especially in BL. Generally it could be shown that to some extend the protein expression differs a lot among different types of B-cell lymphomas and that there was often a significant difference between aggressive and indolent entities. Especially the high protein levels of MTHFD1, MTHFD2 and SHMT2 in highly proliferative lymphomas and their association with poor prognosis point out to a possible essential role of one-carbon metabolism in lymphoma cell proliferation. The same could be shown for ARFGEF2, whose function in the pathogenesis of lymphomas is still unknown as well.
Keywords: lymphoma; Burkitt lymphoma; immunhistochemistry; tissue microarray; b cell receptor signaling; BCR signaling; protein expression; IHC staining; ACTN4; ARFGEF2; BCL11A; CARD11; CDKN1B; MTHFD1; MTHFD2; SHMT2
 
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