RRC ID 70512
Author Jimbo K, Nakajima-Takagi Y, Ito T, Koide S, Nannya Y, Iwama A, Tojo A, Konuma T.
Title Immunoglobulin superfamily member 8 maintains myeloid leukemia stem cells through inhibition of β-catenin degradation.
Journal Leukemia
Abstract 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.
Volume 36(6)
Pages 1550-1562
Published 2022-6-1
DOI 10.1038/s41375-022-01564-7
PII 10.1038/s41375-022-01564-7
PMID 35418614
MeSH Animals Carrier Proteins / metabolism* Frizzled Receptors / metabolism Hematopoietic Stem Cells / metabolism Humans Immunoglobulins Leukemia, Myeloid, Acute* / metabolism Membrane Proteins / metabolism* Mice Neoplastic Stem Cells / pathology Transcription Factors / metabolism beta Catenin / genetics beta Catenin / metabolism*
IF 8.665
Mice RBRC05637