Notch3-regulated microRNAs impair CXCR4-dependent maturation of thymocytes allowing maintenance and progression of T-ALL

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Abstract Malignant transformation of T-cell progenitors causes T-cell acute lymphoblastic leukemia (T-ALL), an aggressive childhood lymphoproliferative disorder. Activating mutations of Notch1 and overexpression of Notch3, as well as rare Notch3 activating mutations have been detected in T-ALL patients. In this study, we aimed to deeply characterize major steps contributing to the progression of T-ALL: hyperactive Notch3-related pathways involved in T-cell dynamics within the thymus and bone marrow infiltration by immature thymocyte subpopulations. We previously generated a transgenic T-ALL mouse model (N3-ICtg) demonstrating that aberrant Notch3 signaling affects early thymocyte maturation programs and leads to bone marrow infiltration by CD4⁺CD8⁺ (DP) T-cells Notch3highCXCR4high. Newly, our in vivo results suggest that an anomalous immature thymocyte subpopulation, such as CD4-CD8- (DN) over-expressing CD3ε, but with low CD5 and CXCR4 expression, dominates N3-ICtg thymus-resident DN subset in T-ALL progression. MicroRNAs might be of significance in T-ALL pathobiology, however, whether required for leukemia maintenance is not fully understood. The selection of specific DN subsets demonstrates the inverse correlation between CXCR4 expression and a panel of Notch3-deregulated miRNAs. Interestingly, we found that hyperactive Notch3 targets CXCR4 expression through the cooperative effects of miR-139-5p and miR-150-5p, and impairs thymocyte differentiation which increases DNCD3ε+CD25+CXCR4- cells that improperly colonize the transgenic BM. These data point out that Notch3 selects specific immature T-cells within the thymus, a reservoir to sustain T-ALL progression.

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