The public defence will be held as a video conference over Zoom.
The defence will follow regular procedure as far as possible, hence it will be open to the public and the audience can ask ex auditorio questions when invited to do so.
Click here to participate in the public defence
Due to copyright reasons, an electronic copy of the thesis must be ordered from the faculty. In order for the faculty to have time to process the order, it must be received by the faculty no later than 2 days prior to the public defence. Orders received later than 2 days before the defence will not be processed. Inquiries regarding the thesis after the public defence must be addressed to the candidate.
Digital Trial Lecture – time and place
Adjudication committee
- First opponent: Senior researcher Francisco Javier Oliver Pozo, Instituto de Parasitologia y Biomedicina López Neyra - CSIC
- Second opponent: Professor Bjørn Tore Gjertsen, Universitetet i Bergen
- Third member and chair of the evaluation committee: Associate Professor June Helen Myklebust, University of Oslo
Chair of the Defence
Professor Finn Olav Levi, Faculty of Medicine, University of Oslo
Principal Supervisor
Professor Heidi Kiil Blomhoff, University of Oslo
Summary
B cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common form of childhood cancer, and it develops from B cell precursors in the bone marrow. In the bone marrow, the cells are exposed to factors and signaling molecules secreted by surrounding cells that may render the BCP-ALL cells less sensitive to cancer therapy. One of these factors is prostaglandin E2 (PGE2) that can induce a cAMP-response in the BCP-ALL cells. Activation of the cAMP signaling pathway renders BCP-ALL cells resistant to DNA damage-induced cell death by involving suppression of p53.
In the present thesis, Nina Richartz and co-workers have established a xenograft model of BCP-ALL in immunocompromised NOD-scidIL2rγnull (NSG) mice. The enzyme cyclooxygenase (COX) is responsible for the conversion of arachidonic acid to PGE2, and BCP-ALL xenograft mice treated with the COX-inhibitor indomethacin showed delayed progression of the leukemia. Furthermore, indomethacin-treated mice had lower levels of serum PGE2, and enhanced expression of p53 in cell lysates from the bone marrow of these mice.
To further study the mechanisms involved in the cAMP-mediated inhibition of DNA damage-induced cell death, Richartz and co-workers demonstrated enhanced levels of autophagy in BCP-ALL cells treated with the cAMP-inducer forskolin. Mechanistically, they revealed that the cAMP-mediated induction of autophagy involved activation of poly (ADP-ribose) polymerase 1 (PARP1), depletion of nicotinamide adenine dinucleotide (NAD) and induction of reactive oxygen species (ROS). Treating the cells with PARP1-inhibitors, exogenous NAD, or the ROS-scavenger NAC, reversed the cAMP-mediated inhibition of DNA damage-induced cell death.
Taken together, the work presented in this thesis has revealed multiple therapeutic targets that can enhance the effect of conventional genotoxic treatments of BCP-ALL. This may enable clinicians to reduce the dosages required to treat the cancer, and thereby limit the severe side effects.
Additional information
Contact the research support staff.