Malignant transformation of T-cell progenitors causes T-cell acute lymphoblastic leukemia (T-ALL),an aggressive childhood lymphoproliferative disorder. Activating mutations of Notch, Notch1 andNotch3, have been detected in T-ALL patients. In this study, we aimed to deeply characterize hyperactive Notch3-related pathways involved in Tcell dynamics within the thymus and bone marrow to propose these processes as an important stepin facilitating the progression of T-ALL. We previously generated a transgenic T-ALL mouse model(N3-ICtg) demonstrating that aberrant Notch3 signaling affects early thymocyte maturation programsand leads to bone marrow infiltration by CD4⁺CD8⁺ (DP) T-cells that are notably, Notch3highCXCR4high.Newly, our in vivo results suggest that an anomalous immature thymocyte subpopulation, such asCD4-CD8- (DN) over-expressing CD3ɛ, but with low CXCR4 expression, dominates N3-ICtg thymusresident DN subset in T-ALL progression. MicroRNAs might be of significance in T-ALL pathobiology,however, whether required for leukaemia maintenance is not fully understood. The selection ofspecific DN subsets demonstrates the inverse correlation between CXCR4 expression and a panel ofNotch3-deregulated miRNAs. Interestingly, we found that within DN thymocyte subset hyperactiveNotch3 inhibits CXCR4 expression through the cooperative effects of miR-139-5p and miR-150-5p,thus impinging on thymocyte differentiation with accumulation of DNCD3ɛ+CXCR4- cells. These datapoint out that deregulation of Notch3 in T-ALL, besides its role in sustaining dissemination ofabnormal DP T cells, as we previously demonstrated, could play a role in selecting specific DNimmature T-cells within the thymus, thus impeding T cell development, to facilitate T-ALL progression inside the bone marrow
Notch3-regulated microRNAs impair CXCR4-dependent maturation of thymocytes allowing maintenance and progression of T-ALL
Russo, Eleonora;Campolo, Federica;
2024-01-01
Abstract
Malignant transformation of T-cell progenitors causes T-cell acute lymphoblastic leukemia (T-ALL),an aggressive childhood lymphoproliferative disorder. Activating mutations of Notch, Notch1 andNotch3, have been detected in T-ALL patients. In this study, we aimed to deeply characterize hyperactive Notch3-related pathways involved in Tcell dynamics within the thymus and bone marrow to propose these processes as an important stepin facilitating the progression of T-ALL. We previously generated a transgenic T-ALL mouse model(N3-ICtg) demonstrating that aberrant Notch3 signaling affects early thymocyte maturation programsand leads to bone marrow infiltration by CD4⁺CD8⁺ (DP) T-cells that are notably, Notch3highCXCR4high.Newly, our in vivo results suggest that an anomalous immature thymocyte subpopulation, such asCD4-CD8- (DN) over-expressing CD3ɛ, but with low CXCR4 expression, dominates N3-ICtg thymusresident DN subset in T-ALL progression. MicroRNAs might be of significance in T-ALL pathobiology,however, whether required for leukaemia maintenance is not fully understood. The selection ofspecific DN subsets demonstrates the inverse correlation between CXCR4 expression and a panel ofNotch3-deregulated miRNAs. Interestingly, we found that within DN thymocyte subset hyperactiveNotch3 inhibits CXCR4 expression through the cooperative effects of miR-139-5p and miR-150-5p,thus impinging on thymocyte differentiation with accumulation of DNCD3ɛ+CXCR4- cells. These datapoint out that deregulation of Notch3 in T-ALL, besides its role in sustaining dissemination ofabnormal DP T cells, as we previously demonstrated, could play a role in selecting specific DNimmature T-cells within the thymus, thus impeding T cell development, to facilitate T-ALL progression inside the bone marrowFile | Dimensione | Formato | |
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