Ring1A and Ring1B maintain murine MOZ-TIF2 AML stem cells by inhibiting expression of Glis2

Eradication of chemotherapy-resistant leukemia stem cells is expected to improve treatment outcomes in patients with acute myelogenous leukemia (AML). In a mouse model of AML expressing the MOZ-TIF2 fusion, we found that Ring1A and Ring1B, components of Polycomb repressive complex 1, play crucial roles in maintaining AML stem cells. Deletion of Ring1A and Ring1B (Ring1A/B) from MOZ-TIF2 AML cells diminished self-renewal capacity and induced the expression of numerous genes including Gli-similar 2 (Glis2). Overexpression of Glis2 caused MOZ-TIF2 AML cells to differentiate into mature cells, whereas Glis2 knockdown in Ring1A/B-deficient MOZ-TIF2 cells inhibited differentiation. Thus, Ring1A/B regulates and maintains AML stem cells in part by repressing Glis2 expression, which promotes their differentiation. These findings provide new insights into the mechanism of AML stem cell homeostasis and reveal novel targets for cancer stem cell therapy. To identify the target genes implicated in the regulation of AML stem cells by PRC1, we performed gene expression profiling in Ring1A-/-;Ring1Bf/f and Ring1A-/-;Ring1BΔ/Δ MOZ-TIF2 cells. Ring1B was conditionally deleted by treating the cells with 4-OHT for 48h or 7days.