SANDESH KUMAR PATEL

Dottore di ricerca

ciclo: XXXV


supervisore: Prof. Maria Pia Felli
co-supervisore: Prof. Giuseppe Giannini

Titolo della tesi: Notch3-regulated microRNAs impair CXCR4-dependent maturation of thymocytes in T-ALL progression

T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive form of cancer caused by the malignant transformation of T-cell progenitors. The primary cause of T-ALL is aberrant Notch receptor signaling, which is commonly associated with mutations in the Notch1 gene and less frequently in the Notch3 gene. In T-ALL patients, mutations in the Notch3 gene are rare. In our transgenic model (N3-ICtg), overexpression of the intracellular active form of the Notch3 receptor induces the development of an aggressive form of T-ALL characterized by the infiltration of lymphoblasts in the bone marrow and spleen. Disruption of Notch3 signaling affects the maturation of early thymocytes, blocking their differentiation and enhancing CXCR4 cell-surface expression on CD4+CD8+/DP cells, which promotes their premature egress from the thymus. As a result, the thymus becomes reduced and fibrous, devoid of DP cells and populated by immature thymocytes. Our in vivo studies have discovered the expansion of an abnormal population of immature early CD4-CD8- thymocytes with low surface expression of CD5, and CXCR4 and with high CD3ε expression, which may serve for T-ALL progression. Considering the role played by CXCR4 in T-cell differentiation and lymphoblasts propagation, we analyzed the epigenetic mechanism/s triggered by hyperactive Notch3 to affect CXCR4 expression in T-ALL progression. Through bioinformatic analysis we individuated three microRNAs (miR): miR139-5p, miR150-5p and miR9-5p which are modulated in our transgenic thymus, and that can target the 3’UTR of CXCR4. Selection of CD4-CD8- (DN) cells from the N3IC-tg thymus, shows an inverse relationship between CXCR4 and the mentioned miRNAs. Additionally, through transfection experiment we assay the effect of exogenously over-expressed miR-150-5p on the endogenous CXCR4 gene expression in a DN T-cell line obtained from N3-ICtg mice. Our findings indicate for the first time that hyperactive Notch3 targets CXCR4 expression by upregulating miR-150-5p expression. Indeed, CXCR4 has been implicated in preselection thymocyte retention in the thymic cortex, thus suggesting a new mechanism of Notch3 to prevent T-cell differentiation. Further studies will help to better understand the crosstalk Notch3/miRs/CXCR4 in T-ALL progression.

Produzione scientifica

  • 11573/1679329 - 2022 - Short-term risk prediction after major lower limb amputation: PERCEIVE study (01a Articolo in rivista)
    BARAKAT, NABIHA HUSSEIN; LAPOLLA, PIERFRANCESCO; SAPIENZA, PAOLO; BRACHINI, GIOIA; MINGOLI, ANDREA; PATEL, SANDESH KUMAR; COSTANZA, MARIA; OBERHUBER, ANDREA; WILLIAMS, CAROLYN S.
  • 11573/1555629 - 2020 - Quercetin acts as a P-gp modulator via impeding signal transduction from nucleotide-binding domain to transmembrane domain (01a Articolo in rivista)
    PATEL, SANDESH KUMAR; GARG, NEHA
  • 11573/1567658 - 2021 - When viruses cross developmental pathways (01g Articolo di rassegna (Review))
    TRIVEDI, PANKAJ; PATEL, SANDESH KUMAR; BELLAVIA, DIANA; MESSINA, ELENA; PALERMO, ROCCO; CECCARELLI, SIMONA; MARCHESE, CINZIA; ANASTASIADOU, ELENI; FELLI, MARIA PIA
  • 11573/1634069 - 2021 - Effect of Protein Corona on the Drug Delivery of Carbogenic Nanodots and Their Mapping by Fluorescence Lifetime Imaging Microscopy (01a Articolo in rivista)
    PATEL, SANDESH KUMAR; GARG, NEHA
  • 11573/1634288 - 2020 - Molecular Aspects of Cancer Cell Metabolism: Altered Glycolysis and Lipid Metabolism (02a Capitolo o Articolo)
    PATEL, SANDESH KUMAR; GARG, NEHA
  • 11573/1427762 - 2019 - Correction to: Imaging of Bronchial Pathology in Antibody Deficiency: Data from the European Chest CT Group (Journal of Clinical Immunology, (2019), 39, 1, (45-54), 10.1007/s10875-018-0577-9) (01a Articolo in rivista)
    MILITO, CINZIA; MITREVSKI, MILICA; QUINTI, ISABELLA; SPADARO, GIUSEPPE; METZ, FERNANDO LUCAS; PATEL, SANDESH KUMAR
  • 11573/1659861 - 2020 - Safety of hospital discharge before return of bowel function after elective colorectal surgery (01a Articolo in rivista)
    SAGNOTTA, ANDREA; PARINI, DIEGO; MARTIN, PETRA; LA TORRE, FILIPPO; COLANGELO, ETTORE; SAGNOTTA, ANDREA; DESIDERIO, JACOPO; LAPOLLA, PIERFRANCESCO; COLETTA, DIEGO; CIRILLO, BRUNO; DE TOMA, GIORGIO; GALLO, GAETANO; LICARI, LESLIE CLAIRE; CERRA, CATIA; PATEL, SANDESH KUMAR

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