Intrathymic Notch3 and CXCR4 combinatorial interplay facilitates T-cell leukemia propagation

Francesca Ferrandino, Giovanni Bernardini, Georgia Tsaouli, Paola Grazioli, Antonio Francesco Campese, Claudia Noce, Ambra Ciuffetta, Alessandra Vacca, Zein Mersini Besharat, Diana Bellavia, Isabella Screpanti, Maria Pia Felli

Research output: Contribution to journalArticlepeer-review

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+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 β-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.

Original languageEnglish
Pages (from-to)6285-6298
Number of pages14
JournalOncogene
Volume37
Issue number49
DOIs
Publication statusPublished - Dec 6 2018

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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