Effect of A20 deletion in a retroviral mouse model of AML
We show that AML patients who experience induction failure have elevated expression of the NF-kB target gene TNFAIP3/A20 and impaired necroptotic cell death, leading to a worse prognosis with chemotherapy. A20High AML samples display resistance to anthracyclines, while A20Low AML samples show sensitivity. Loss of A20 in AML cells restores sensitivity to anthracycline treatment by inducing necroptosis. Moreover, our studies revealed that A20 plays a critical role in AML development as deletion or knockdown of A20 effectively suppresses leukemic cells by mediating spontaneous necroptosis. A20 prevents necroptosis in AML by targeting the necroptosis effector RIPK1, and anthracycline-induced necroptosis is abrogated in A20High AML cells. These findings suggest that NF-kB-driven A20 overexpression plays a role in failed chemotherapy induction and highlights the potential of targeting an alternative cell death pathway in AML. The data contained here provide a platform in which to examine the effects of A20 loss in a retroviral mouse model of AML. Overall design: A retroviral mouse model of AML was generated by transducing lineage negative hematopoietic cells from A20+/+ Rosa Cre-ER and A20f/f Rosa Cre-ER mice with the oncogene MLL-AF9. Cells were treated with 1uM 4-hydoxy-tamoxifen for 48hr to induce deletion of A20 at which point they were harvested and RNA was isolated.