Work package 3.  B-cell lymphoma (BCL)

Work package leader: Dr. Jeroen Guikema.

 

Research question: What is the precise role of the germinal center (GC) reaction in B-cell tumorigenesis?


Several of the most frequent B-cell cancer subtypes are considered of GC B-cell origin, indicating that GCR shutdown failure lies at the core of their genesis and evolution. B-cell lymphoma (BCL) of postulated GC origin, including diffuse large B-cell lymphoma, follicular lymphoma and a subset of chronic lymphocytic leukemia, exhibit somatic hypermutation (SHM) patterns typical of B cells that have undergone selection by antigen. This is often accompanied by intraclonal diversification due to SHM arising in a context of ongoing antigen interactions, while at least some BCL display in vivo class switch recombination (CSR). Alltogether attesting to the importance of the GCR in their genesis and progression. Moreover, these neoplasias are characterised by recurrent gene mutations/translocations that, at least in part, stem from aberrant and/or off-target SHM and/or CSR . In particular, error-prone DNA repair activities that are characteristic for GC B cells by enabling B-cell receptor (BCR) diversification, facilitate the acquisition of secondary genetic alterations ultimately causing malignant transformation. Most experimental (mouse) models for BCL focus on the endpoints of malignant B-cell transformation, whereas the early stages of GC-derived B-cell tumorigenesis are poorly understood, and efforts to reconstruct the multistep process of tumorigenesis have been rather limited. Moreover, the GC B-cell specific regulation of DNA repair fidelity, and the effects of GC B-cell specific oncogene overexpression on GCR resolution (embodying the early stages of tumorigenesis) remain largely uncharted.

COSMIC aims to provide a high-resolution framework of molecular, cellular and clonal dynamics of the normal and BCL GCR, assess the GC-specific regulation of DNA repair activities, and to assess the effects of overexpression of BCL-associated oncogenes in the GC. We expect that this will lead to biomarkers that predict onset of BCL, and to molecular pathways essential for BCL growth and maintenance that can be targeted with (new) drugs. The expression and/or activity of the identified biomarkers will be validated and tested in human BCL patient samples and normal human lymphoid tissues containing GCs (reactive lymph node and tonsil).

Expected results: Novel mechanistic insight into the role of the GCR in B-cell tumorigenesis, identification of crucial factors/steps that determine transformation, growth, and maintenance of malignant GC B cells. Novel therapeutic biomarkers and drug targets.

 

Go to Work package overview 


 

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