| First Author | Sergio I | Year | 2024 |
| Journal | Oncogene | Volume | 43 |
| Issue | 34 | Pages | 2535-2547 |
| PubMed ID | 38907003 | Mgi Jnum | J:353563 |
| Mgi Id | MGI:7715308 | Doi | 10.1038/s41388-024-03079-0 |
| Citation | Sergio I, et al. (2024) Notch3-regulated microRNAs impair CXCR4-dependent maturation of thymocytes allowing maintenance and progression of T-ALL. Oncogene 43(34):2535-2547 |
| abstractText | Malignant transformation of T-cell progenitors causes T-cell acute lymphoblastic leukemia (T-ALL), an aggressive childhood lymphoproliferative disorder. Activating mutations of Notch, Notch1 and Notch3, have been detected in T-ALL patients. In this study, we aimed to deeply characterize hyperactive Notch3-related pathways involved in T-cell dynamics within the thymus and bone marrow to propose these processes as an important step in 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 programs and leads to bone marrow infiltration by CD4(+)CD8(+) (DP) T cells that are notably, Notch3(high)CXCR4(high). Newly, our in vivo results suggest that an anomalous immature thymocyte subpopulation, such as CD4(-)CD8(-) (DN) over-expressing CD3varepsilon, but with low 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 within DN thymocyte subset hyperactive Notch3 inhibits CXCR4 expression through the cooperative effects of miR-139-5p and miR-150-5p, thus impinging on thymocyte differentiation with accumulation of DNCD3varepsilon(+)CXCR4(-) cells. These data point out that deregulation of Notch3 in T-ALL, besides its role in sustaining dissemination of abnormal DP T cells, as we previously demonstrated, could play a role in selecting specific DN immature T cells within the thymus, thus impeding T cell development, to facilitate T-ALL progression inside the bone marrow. |
