Kruse, Vanessa

Burkitt’s lymphoma (BL) is an aggressive B cell neoplasm that is characterized by a chromosomal
translocation, which brings the proto-oncogene c-MYC under the control of Immunoglobulin (Ig)
enhancer elements leading to c-MYC overexpression. While high levels of c-MYC are important for
the proliferation of BL cells, c-MYC overexpression leads to apoptosis in non-malignant cells. Studies
have identified the pro-survival Phosphoinositide-3-kinase (PI3K)-AKT pathway to be continuously
activated in BL cells and more recently it was shown that this pathway is activated by low levels of
antigen-independent, tonic B cell antigen receptor (BCR) signals. During B cell development,
continuous tonic BCR signaling is necessary for maturation and survival of B cells. Similar to its
physiological function, tonic BCR signaling in BL contributes to survival of malignant BL cells. While
we know that tonic BCR signals activate the PI3K-AKT pathway, the BCR-proximal molecular
networks regulating tonic BCR signaling are less well defined. The goal of this thesis was therefore
to characterize new BL-specific BCR effector proteins previously identified by phospho-proteomic
approaches for their contribution to survival of BL cells with respect to tonic BCR signaling.
In this thesis, BL-specific effector proteins were selected based on previous reports stating their role
for PI3K-AKT BCR signaling or based on a potential survival relevant role established in preliminary
shRNA screens. CRISPR/Cas9 “knockout” BL cell lines for the adaptor proteins Nck1 and Nck2 as well
as the guanine nucleotide exchange factor BIG2 and the inositol-5’ phosphatase SHIP2 showed a
decline in proliferation. For Nck1- and Nck2-deficient cells, the proliferative defect could be linked
to a decrease in PI3K-AKT signaling mediated by tonic BCR signals, thus identifying Nck proteins as
novel, proximal regulators of tonic BCR-dependent PI3K-AKT signaling. Moreover, I identified SHIP2
and BIG2 being relevant for BL survival as their absence increased apoptosis of BL cell lines, which,
for BIG2, was accompanied by decreased c-MYC expression levels. Despite their survival relevant
role, SHIP2 and BIG2 were identified as negative regulators of AKT signaling, thereby contrasting
previous beliefs that survival of BL cells was mainly dependent on the PI3K-AKT pathway. BL-effectors analyzed here promoted signaling via the Mitogen-activated protein kinase (MAPK) c-Jun
N-terminal kinase (JNK) pathway, indicating the relevance for this pathway for BL. Despite findings
that JNK activation promotes apoptosis in other cell types, JNK was shown to have a unique pro-survival role in B cell malignancies. Here, I provide evidence that tonic BCR signals also involve JNK
signaling and that the analyzed BL-effector proteins are regulators in this pro-survival pathway.
Therefore, the identified effectors may not only be new therapeutic targets themselves but also
revealed a novel, potentially druggable pathway dependent on tonic BCR signaling in BL

Georg-August-University Göttingen

Identification of therapeutic targets in the Burkitt’s lymphoma specific B cell antigen receptor signaling network

https://ediss.uni-goettingen.de/bitstream/11858/00-1735-0000-002E-E4FA-4/1/181017%20Thesis_Kruse_ePub.pdf

Identification of therapeutic targets in the Burkitt’s lymphoma specific B cell antigen receptor signaling network

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Georg-August-University Göttingen