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

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...

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Published in:Oncogene 2024-08, Vol.43 (34), p.2535-2547
Main Authors: Sergio, Ilaria, Varricchio, Claudia, Patel, Sandesh Kumar, Del Gaizo, Martina, Russo, Eleonora, Orlando, Andrea, Peruzzi, Giovanna, Ferrandino, Francesca, Tsaouli, Georgia, Coni, Sonia, Peluso, Daniele, Besharat, Zein Mersini, Campolo, Federica, Venneri, Mary Anna, Del Bufalo, Donatella, Lai, Silvia, Indraccolo, Stefano, Minuzzo, Sonia, La Starza, Roberta, Bernardini, Giovanni, Screpanti, Isabella, Campese, Antonio Francesco, Felli, Maria Pia
Format: Article
Language:English
Subjects:
Acute lymphoblastic leukemia
Bone marrow
CD4 antigen
CD8 antigen
Cell differentiation
Children
CXCR4 protein
Genetic transformation
Leukemia
Lymphocytes
Lymphocytes T
Maturation
MicroRNAs
miRNA
Notch1 protein
Progenitor cells
Thymocytes
Thymus
Thymus gland
Transgenic mice
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Summary: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, Notch3highCXCR4high. Newly, our in vivo results suggest that an anomalous immature thymocyte subpopulation, such as CD4−CD8− (DN) over-expressing CD3ɛ, 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 DNCD3ɛ+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.
ISSN:0950-9232
1476-5594
1476-5594
DOI:10.1038/s41388-024-03079-0