| 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
|
| Resource |
| Mice |
RBRC05637 |
