A Fibrinogen Alpha Fragment Mitigates Chemotherapy-Induced MLL Rearrangements
نویسندگان
چکیده
Rearrangements in the Mixed Lineage Leukemia breakpoint cluster region ( MLL bcr) are frequently involved therapy-induced leukemia, a severe side effect of anti-cancer therapies. Previous work unraveled Endonuclease G as critical nuclease causing initial breakage bcr response to different types chemotherapeutic treatment. To identify peptides protecting against we screened hemofiltrate-derived peptide library by use an enhanced green fluorescent protein (EGFP)-based chromosomal reporter rearrangements. Chromatographic purification one active fraction and subsequent mass spectrometry allowed isolate C-terminal 27-mer fibrinogen α encompassing amino acids 603 629. The chemically synthesized peptide, termed Fα27, inhibited rearrangements immortalized hematopoietic cells following treatment with cytostatics etoposide or doxorubicin. We also provide evidence for protection primary human stem progenitor from breakage. Of note, has been described activate toll-like receptor 4 (TLR4). Dissecting Fα27 mode-of action revealed association TLR4 antagonistic fashion affecting downstream NFκB signaling pro-inflammatory cytokine production. In conclusion, identified inhibitor genome destabilizing events secondary leukemia patients undergoing chemotherapy.
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ژورنال
عنوان ژورنال: Frontiers in Oncology
سال: 2021
ISSN: ['2234-943X']
DOI: https://doi.org/10.3389/fonc.2021.689063