Journal
LEUKEMIA
Volume 36, Issue 6, Pages 1550-1562Publisher
SPRINGERNATURE
DOI: 10.1038/s41375-022-01564-7
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Funding
- RIKEN BRC through the National BioResource Project of the MEXT/AMED, Japan [RBRC05637]
- SGH foundation
- Japanese Society of Hematology Research Grant
- Princess Takamatsu Cancer Research Fund
- Cooperative Research Program (Joint Usage/Research Center program) of Institute for Frontier Life and Medical Sciences, Kyoto University
- Japan Society for the Promotion of Science (JSPS) KAKENHI [20K08748, 20J10521, 19H05746]
- JSPS
- Grants-in-Aid for Scientific Research [20J10521, 20K08748, 19H05746] Funding Source: KAKEN
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The role of Igsf8 in normal and malignant hematopoietic stem cells was investigated using a conditional knockout model. Deletion of Igsf8 improved survival in mouse myeloid leukemia models by depleting leukemia stem cells through enhanced apoptosis and beta-catenin degradation. Activation of beta-catenin in leukemia stem cells depends on Igsf8, which promotes the association of FZD4 with its co-receptor LRP6.
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 beta-catenin degradation. At a molecular level, we found that activation of beta-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.
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