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Intrathymic Notch3 and CXCR4 combinatorial interplay facilitates T-cell leukemia propagation.
- Source :
-
Oncogene [Oncogene] 2018 Dec; Vol. 37 (49), pp. 6285-6298. Date of Electronic Publication: 2018 Jul 23. - Publication Year :
- 2018
-
Abstract
- 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 <superscript>+</superscript> CD8 <superscript>+</superscript> 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 <superscript>+</superscript> CD8 <superscript>+</superscript> cells, characterized by high and combined surface expression of Notch3 and CXCR4. We report for the first time that transplantation of such CD4 <superscript>+</superscript> CD8 <superscript>+</superscript> 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 <superscript>+</superscript> CD8 <superscript>+</superscript> cells and such an expression is regulated by Notch3 through β-arrestin in human leukemia cells. De novo, we propose that hyperactive Notch3 signaling by boosting CXCR4-dependent migration promotes anomalous egression of CD4 <superscript>+</superscript> CD8 <superscript>+</superscript> cells from the thymus in early leukemia stages. In fact, in vivo CXCR4 antagonism prevents bone marrow colonization by such CD4 <superscript>+</superscript> CD8 <superscript>+</superscript> 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 <superscript>+</superscript> CD8 <superscript>+</superscript> cells, by a "thymus-autonomous" mechanism.
- Subjects :
- Animals
CD4-Positive T-Lymphocytes metabolism
CD8-Positive T-Lymphocytes metabolism
Cell Movement physiology
Cell Transformation, Neoplastic metabolism
Cell Transformation, Neoplastic pathology
Humans
Mice
Mice, Transgenic
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma metabolism
CD4-Positive T-Lymphocytes pathology
CD8-Positive T-Lymphocytes pathology
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma pathology
Receptor, Notch3 metabolism
Receptors, CXCR4 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5594
- Volume :
- 37
- Issue :
- 49
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 30038265
- Full Text :
- https://doi.org/10.1038/s41388-018-0401-2