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 leukaemia 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
Notch3-regulated microRNAs impair CXCR4-dependent maturation of thymocytes allowing maintenance and progression of T-ALL / 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. - In: ONCOGENE. - ISSN 0950-9232. - (2024). [10.1038/s41388-024-03079-0]
Notch3-regulated microRNAs impair CXCR4-dependent maturation of thymocytes allowing maintenance and progression of T-ALL
Ilaria SergioCo-primo
Writing – Original Draft Preparation
;Claudia VarricchioCo-primo
;Sandesh Kumar PatelCo-primo
;Eleonora Russo;Giovanna Peruzzi;Georgia Tsaouli;Sonia Coni;Zein Mersini Besharat;Federica Campolo;Mary Anna Venneri;Silvia Lai;Giovanni Bernardini;Isabella Screpanti;Antonio Francesco CampesePenultimo
Writing – Review & Editing
;Maria Pia Felli
Ultimo
Writing – Review & Editing
2024
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 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 leukaemia 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 marrowI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.