p53 independent epigenetic-differentiation treatment in xenotransplant models of acute myeloid leukemia

摘要: Suppression of apoptosis by TP53 mutation contributes to resistance acute myeloid leukemia (AML) conventional cytotoxic treatment. Using differentiation induce irreversible cell cycle exit in AML cells could be a p53-independent treatment alternative, however, this possibility requires evaluation. In vitro and vivo regimens the cytosine analogue decitabine that deplete chromatin modifying enzyme DNA methyl-transferase 1 (DNMT1) without phosphorylating p53 or inducing early were determined. These but not equimolar DNA-damaging cytarabine up regulated key late factors CEBPx p27/CDKN1B, induced cellular differentiation, terminated cell-cycle, even cytarabine-resistant p53- p16/CDKN2A-null cells. Leukemia initiation xeno-transplanted was abrogated normal hematopoietic stem (HSC) engraftment preserved. vivo, low toxicity allowed frequent drug administration increase exposure, an important consideration for S-phase specific therapy. xeno-transplant models p53-null relapsed/refractory AML, non-cytotoxic regimen significantly extended survival compared cytarabine. Modifying dose schedule emphasize pathway action can bypass mechanism standard