| First Author | Ferrandino F | Year | 2018 |
| Journal | Oncogene | Volume | 37 |
| Issue | 49 | Pages | 6285-6298 |
| PubMed ID | 30038265 | Mgi Jnum | J:267436 |
| Mgi Id | MGI:6259403 | Doi | 10.1038/s41388-018-0401-2 |
| Citation | Ferrandino F, et al. (2018) Intrathymic Notch3 and CXCR4 combinatorial interplay facilitates T-cell leukemia propagation. Oncogene |
| abstractText | Notch hyperactivation dominates T-cell acute lymphoblastic leukemia development, but the mechanisms underlying "pre-leukemic" cell dissemination are still unclear. Here we describe how deregulated Notch3 signaling enhances CXCR4 cell-surface expression and migratory ability of CD4(+)CD8(+) thymocytes, possibly contributing to "pre-leukemic" cell propagation, early in disease progression. In transgenic mice overexpressing the constitutively active Notch3 intracellular domain, we detect the progressive increase in circulating blood and bone marrow of CD4(+)CD8(+) cells, characterized by high and combined surface expression of Notch3 and CXCR4. We report for the first time that transplantation of such CD4(+)CD8(+) cells reveals their competence in infiltrating spleen and bone marrow of immunocompromised recipient mice. We also show that CXCR4 surface expression is central to the migratory ability of CD4(+)CD8(+) cells and such an expression is regulated by Notch3 through beta-arrestin in human leukemia cells. De novo, we propose that hyperactive Notch3 signaling by boosting CXCR4-dependent migration promotes anomalous egression of CD4(+)CD8(+) cells from the thymus in early leukemia stages. In fact, in vivo CXCR4 antagonism prevents bone marrow colonization by such CD4(+)CD8(+) cells in young Notch3 transgenic mice. Therefore, our data suggest that combined therapies precociously counteracting intrathymic Notch3/CXCR4 crosstalk may prevent dissemination of "pre-leukemic" CD4(+)CD8(+) cells, by a "thymus-autonomous" mechanism. |
