The identification of distinctive distinctions between cancer stem cells and normal counterparts, which is a significant problem for cancer therapy, has been reinforced. The immunoglobulin superfamily member 8 (Igsf8, also known as EWI-2, PGRL, and CD316) was investigated in this study for its part in normal and malignant hematopoietic stem cells, using a conditional knockout approach. Deleting Igsf8 had no significant impact on steady state hematopoiesis, but it substantially improved mouse myeloid leukemia animal models’ survival. Through enhanced apoptosis and β-catenin degradation, Igsf8 excision deprives leukemia stem cells (LSCs) of their viability. The researchers discovered that the interaction of FZD4 with its co-receptor LRP6 is promoted by Igsf8 in the presence of Igsf8, which led to the activation of β-catenin at a molecular level. In addition, IGSF8 inhibition impeded LSC colony formation and improved survival of myeloid leukemia transplant recipients in xenograft models. The data indicated strong genetic evidence that Igsf8 is a critical regulator of myeloid leukemia and that interfering with IGSF8 may have provided a novel therapeutic approach against myeloid leukemia.