Rearrangements in the Mixed Lineage
Leukemia breakpoint cluster region (MLLbcr) are frequently involved in
therapy-induced
leukemia, a severe side effect of anti-
cancer therapies. Previous work unraveled
Endonuclease G as the critical nuclease causing initial breakage in the MLLbcr in response to different types of chemotherapeutic treatment. To identify
peptides protecting against
therapy-induced
leukemia, we screened a hemofiltrate-derived
peptide library by use of an
enhanced green fluorescent protein (EGFP)-based chromosomal reporter of MLLbcr rearrangements. Chromatographic purification of one active fraction and subsequent mass spectrometry allowed to isolate a C-terminal 27-mer of
fibrinogen α encompassing
amino acids 603 to 629. The chemically synthesized
peptide, termed Fα27, inhibited MLLbcr rearrangements in immortalized hematopoietic cells following treatment with the
cytostatics etoposide or
doxorubicin. We also provide evidence for protection of primary human hematopoietic stem and progenitor cells from
therapy-induced MLLbcr breakage. Of note,
fibrinogen has been described to activate
toll-like receptor 4 (TLR4). Dissecting the Fα27 mode-of action revealed association of the
peptide with TLR4 in an antagonistic fashion affecting downstream NFκB signaling and pro-inflammatory
cytokine production. In conclusion, we identified a hemofiltrate-derived
peptide inhibitor of the genome destabilizing events causing secondary
leukemia in patients undergoing
chemotherapy.