Immunoglobulin superfamily member 8 maintains myeloid leukemia stem cells through inhibition of β-catenin degradation

• Published in: Leukemia Vol. 36; no. 6; pp. 1550 - 1562
• Main Authors: Jimbo, Koji, Nakajima-Takagi, Yaeko, Ito, Takahiro, Koide, Shuhei, Nannya, Yasuhito, Iwama, Atsushi, Tojo, Arinobu, Konuma, Takaaki
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.06.2022
• Subjects: Animal models; Apoptosis; Cancer; Degradation; Deletion; Hematopoiesis; Hematopoietic stem cells; Immunoglobulins; Leukemia; Myeloid leukemia; Stem cell transplantation; Stem cells; Survival; Xenografts; Xenotransplantation; β-Catenin
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-022-01564-7

The identification of characteristic differences between cancer stem cells and their normal counterparts remains a key challenge for cancer treatment. Here, we investigated the role of immunoglobulin superfamily member 8 (Igsf8, also known as EWI-2, PGRL, and CD316) on normal and malignant hematopoietic stem cells, mainly using the conditional knockout model. Deletion of Igsf8 did not affect steady state hematopoiesis, but it led to a significant improvement of survival in mouse myeloid leukemia models. Deletion of Igsf8 significantly depletes leukemia stem cells (LSCs) through enhanced apoptosis and β-catenin degradation. At a molecular level, we found that activation of β-catenin in LSCs depends on Igsf8, which promotes the association of FZD4 with its co-receptor LRP6 in the presence of Igsf8. Similarly, IGSF8 inhibition blocks the colony-forming ability of LSCs and improves the survival of recipients in xenograft models of myeloid leukemia. Collectively, these data indicate strong genetic evidence identifying Igsf8 as a key regulator of myeloid leukemia and the possibility that targeting IGSF8 may serve as a new therapeutic approach against myeloid leukemia.