Identification and mechanism of human peptides protecting against therapy-induced leukemia

Secondary leukemia is a side effect of chemotherapeutic treatment that can occur several years after initial therapy, e.g. doxorubicin or etoposide. Etoposide as well as other drugs like doxorubicin can induce secondary leukemia, which is known for poor prognosis of the affected patients. It was shown that Endonuclease G is involved in the cleavage of the mixed linage-leukemia breakpoint cluster region (MLLbcr) during aphidicolin treatment, which causes replication stress. In the first part of the project the mode-of-action of Fα27 peptide was discovered, which decreases MLLbcr rearrangements and affects EndoG localization on MLLbcr. Furthermore, an interaction between TLR4 and Fα27 was shown leading to a decreased activation of TLR4 impacting on the EndoG-MLLbcr interplay. In the second part of the project natural EndoG inhibitors, which exist in lower organisms, were of interest. The C-terminal part of the DNA repair protein Ku80 shows structural similarities to these natural EndoG inhibitors. This region of Ku80 decreases MLLbcr rearrangements and protects the MLLbcr against breakage. Based on this sequence a Ku3 peptide was designed showing a MLLbcr protective effect by reducing site-specific breakage and rearrangements after doxorubicin treatment. In summary, different human peptides were discovered decreasing MLLbcr rearrangements.