Targeting central B cell tolerance checkpoints in acute lymphoblastic leukemia

• Applicant: Dr. Franziska Auer
• Subject Area: Hematology, Oncology
• Term: from 2017 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 399284630

Over the last century, significant progress has been made in the treatment of B cell precursor acute lymphoblastic leukemia (pre-B ALL) in childhood. Nevertheless, the standard treatment regimens are intense with high toxicities and the survival for poor responders or relapse patients remains low. In order to further improve current treatment strategies, it is crucial to implement novel therapeutic options that directly target the malignant cell type. The here proposed project supports a new approach which uses the body’s own intrinsic immune system to clear malignantly transformed pre-B cells by utilizing central B cell tolerance checkpoint (BTC)-activation. This strategy is based on the concept that cancerous pre-B cells still depend on the same precursor B cell receptor (pre-BCR) signaling machinery like normal pre-B cells for survival and progression. While current treatments, like tyrosine kinase inhibitors (TKIs), employ the “death-by-neglect” principle in inhibiting the constitutively active pre-BCR signaling of the transformed cell, BTC-activation uses the reverse approach. Thus, instead of suppressing the survival signals, massive hyperactivation of the pre-BCR pathway leads to clearance of malignant pre-B cells by mimicking the intrinsic mechanism of establishing B cell tolerance. Previous works from the host group could already show impressive results supporting the concept of BTC-activation for pre-B ALL. Therefore, I want to tie in with their previous findings and further elucidate a potential application of BTC-agonists. In this proposal I want the carry out pre-clinical testing of BTC-activation in pre-B ALL, test its potential to overcome drug resistance and explore energy crisis as a potential mechanism of BTC-induced cell death.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Markus Müschen