RNA腺苷脱氨酶在MLL-AF9诱导的小鼠急性髓系白血病发病中的作用

OBJECTIVE: To establish the ADAR1 (adenosine deaminase that act on RNA 1) knockout MLL-AF9 acute myeloid leukemia (AML) mouse model, and to preliminarily investigate the effects of ADAR1 deletion on the development of AML. METHODS: The lineage(−)(Lin(−)) cells of ER-CreADAR1(lox/lox) mice and their ADAR1(lox/lox) counterparts were enriched by magnetic activated cell sorting (MACS) and then transduced with retrovirus carrying MSCV-MLL/AF9-IRES-GFP fusion gene. The efficiency of transduction was detected by flow cytometry, and equal number of GFP(+) cells were transplanted into lethally irradiated recipient mice. The recipient mice were treated with tamoxifen at 48 hours after transplantation to induce ADAR1 knockout and divided into following groups: experimental group (ER-Cre;ADAR1(lox/lox)+tamoxifen), control groups (①ER-Cre;ADAR1(lox/lox)+vechile, ②ADAR1(lox/lox)+ tamoxifen, ③ADAR1(lox/lox)+vechile). The percentage of GFP(+) cells in peripheral blood was examined at 10, 15 and 20 days respectively after transplantation and the survival of the recipient mice was observed. In vitro study, ER-Cre;ADAR1(lox/lox) and ADAR1(lox/lox) AML cells were cultured and the apoptosis rates of these cells 48 hours after 4-hydroxytamoxifen treatment were examined. RESULTS: The ADAR1 deletion MLL-AF9 AML mouse model was successfully established. Deletion of ADAR1 could decrease the percentage of GFP(+) cells in the peripheral blood and significantly prolong the survival rate of recipient mice (P<0.05). In vitro study showed that the cultured total cell number, percentage of GFP(+) cells decreased and the apoptosis rate of AML cells increased. CONCLUSION: Ablation of ADAR1 could delay the progression of AML in recipient mice. ADAR1 plays a critical role in the development and maintenance of murine MLL-AF9 AML.