Leukemogenic rearrangements at the mixed lineage leukemia gene (MLL)—multiple rather than a single mechanism

摘要: Despite manifold efforts to achieve reduced-intensity and -toxicity regimens, secondary leukemia has remained the most severe side effect of chemotherapeutic cancer treatment. Rearrangements involving a short telomeric <1kb region mixed lineage (MLL) gene are frequently observed molecular changes in as well infant acute leukemia. Due mode-of-action epipodophyllotoxins anthracyclines, which have widely been used therapy, support from vitro experiments, cleavage this MLL breakpoint cluster hotspot by poisoned topoisomerase II was proposed trigger events leading malignant transformation. Later on, clinical patient data cell-based studies addressing wider spectrum stimuli identified cellular stress signaling pathways, create DNA structures, provide chromatin accessibility, activate nucleases other than at MLL. The destabilizing pathways under discussion, namely early apoptotic fragmentation, transcription stalling, replication may all act concert upon infection-, transplantation-, or therapy-induced cell cycle entry hematopoietic stem progenitor cells, permit misguided error-prone repair cell-of-leukemia-origin.