The enzymatic product of SH2 domain-containing inositol 5-phosphatases supports the fitness of BCR-dependent Burkitt lymphoma cells by promoting the energy metabolism
von Florian Mayr
Datum der mündl. Prüfung:2023-11-13
Erschienen:2023-11-23
Betreuer:Prof. Dr. Jürgen Wienands
Gutachter:Prof. Dr. Jürgen Wienands
Gutachter:Dr. Alex Caspar Faesen
Dateien
Name:PhD_Thesis_Online.pdf
Size:25.0Mb
Format:PDF
Zusammenfassung
Englisch
Burkitt lymphoma (BL) is an aggressively growing neoplasm owing to an over expression of the MYC oncogene and exploitation of the tonic B cell receptor (BCR) signaling for its survival. While it is known that the survival signaling is mediated by the phosphoinositide- 3-kinase (PI3K), the details of the rewired BL-specific BCR signaling network remain poorly understood. A small-hairpin RNA (shRNA) based loss of function screen revealed that the SH2 domain-containing 5-inositol phosphatase 2 (SHIP2) potentially influences the survival of BL cells. Generation and characterisation of multiple SHIP2-deficient BL cell lines revealed a perturbed proliferation and increased apoptosis. Furthermore, these effects could not be observed in a surface BCR-negative BL cell line, suggesting that SHIP2 activity is regulated by tonic BCR signaling. SHIP2 is generally described as a negative regulator of AKT activity, but the phosphorylation levels of AKT remained stable in the absence of SHIP2. Similarly, the activation of mitogen-activated protein kinases (MAPK) were unaltered. In contrast, SHIP2 deficiency attenuated the ATP production independently of glucose uptake. It was found that the enzymatic product of SHIP2, phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2), is required for an efficient energy metabolism. In addition, SHIP2-deficient cells exhibited lowered aspartate levels, possibly due to inefficient glycolysis. Further, interference with the function of SHIP1 mirrored the effects observed in SHIP2-deficient cells, indicating a redundant function. Consistently, interruption of SHIP1/2 activity in BL cell lines augmented the susceptibility to inhibition of survival signaling mediated by the PI3K. This study provides a molecular basis describing how tonic BCR signals are linked to an efficient energy metabolism, which is particularly necessary to fuel a fast growing tumor such as BL. Moreover, these discoveries may serve as a basis to potentially enhance the treatment efficiency of BL by targeting the energy supply through the inhibition of SHIP proteins, thus increasing the vulnerability to targeting survival signals.
Keywords: Immunology; Burkitt Lymphoma; B cell receptor; Signal Transduction; Inositol phosphatase