Il1rl1, also known as ST2, encodes the ST2 receptor for IL-33, an important cytokine in inflammation regulation. The IL-33/Il1rl1 axis is involved in multiple biological processes and disease-related pathways, playing a crucial role in immune responses and cell survival regulation [2,3].

In acute myeloid leukemia (AML), using a Cbfb-MYH11 knock-in mouse model, it was shown that Il1rl1 is dynamically expressed on Cbfb-MYH11+ leukemia stem cells. Treatment with IL-33, the ligand of Il1rl1, increased serial replating ability and expression of pro-survival proteins in vitro, and Il1rl1+ cells survived chemotherapy better in vivo [2]. Further study demonstrated that the IL-33/Il1rl1 axis in AML cells decreased drug sensitivity, increased the expression of IL-4 and IL-6, activated p38 MAPK and NF-κB, decreased apoptosis, and the MAPK inhibitor could reverse these effects [4]. In the tumor microenvironment, Il1rl1 signaling in regulatory T (Treg) cells dampened the antitumor activity of IL-33 and PD-1 blockade. The amphiregulin (AREG)-epidermal growth factor receptor (EGFR) axis mediated cross-talk between Il1rl1+ Treg cells and cancer-associated fibroblasts (CAFs), and AREG mAbs and IL-33 could concertedly inhibit tumor growth [1].

In conclusion, Il1rl1, through its interaction with IL-33, is crucial in regulating cell survival in AML and plays a significant role in the tumor microenvironment, influencing antitumor immunity. Mouse models, such as the Cbfb-MYH11 knock-in mouse model, have been instrumental in revealing these functions, providing valuable insights into the pathogenesis of leukemia and cancer immunotherapy [1,2,4].