Background: The Notch3 deregulation inside T-cell compartment of transgenic (N3-tg) mice, induces an aggressive form of T-cell acute lymphoblastic leukemia (T-ALL), strongly sustained by an NF-κB constitutive activation, mainly represented by the p50/p65-dependent canonical pathway. To clarify the Notch/NF-κB relationships in the onset/progression of T-ALL, we decided to inhibit NF-κB canonical pathway in N3-tg mice. Methods: We generated N3-tg/p50-/- mice, deleted of the NF-κB/p50 subunit in a Notch3 transgenic background. The follow-up of N3-tg/p50-/- versus N3- tg mice was conducted and hematopoietic cell analysis was performed at different ages and in multiple tissues from the indicated animals by flow-cytometry techniques. Results: The p50 deletion inhibited the progression of T-ALL in N3-tg/p50-/- mice, as defined primarily by the peripheral expansion of immature CD4+CD8+ T cells. Surprisingly, the double mutant mice succumb earlier than N3-tg counterparts. Moribund N3-tg/p50-/- mice display the trait of a myeloproliferative disease, with the dramatic expansion of Mac1+Gr1+ myeloid cells in both spleen and blood, as well as of granulocyte/monocyte progenitors in the bone marrow. Preliminary data indicate that these cells do not express Notch3, suggesting that in the absence of p50 expression, Notch3 is able to mainly influence the equilibrium of the myeloid compartment in trans. Conclusions: The results presented suggest that the ablation of NF-κB canonical pathway may strongly impact on the outcomes of a T cell specific deregulation of Notch signaling. Thus, providing a useful experimental model to extend our understanding of Notch/NF-κB interplay and to unravel novel strategies for the therapy of different hematological malignancies.

The Outcome of Notch3-dependent T Cell Leukemia Is Modified By NF-kappaB Deletion / Campese, Antonio Francesco; Grazioli, Paola; Scafetta, Gaia; Noce, Claudia; Verkhovskaia, Sofia; C., Mari; Felli, MARIA PIA; Gulino, Alberto; Screpanti, Isabella. - In: THE AMERICAN JOURNAL OF PATHOLOGY. - ISSN 0002-9440. - ELETTRONICO. - 18:3 Suppl(2012), pp. 24-24. (Intervento presentato al convegno XXXI Congress of the Italian Society of Pathology and Translational Medicine tenutosi a Udine, Italia nel sep, 2012).

The Outcome of Notch3-dependent T Cell Leukemia Is Modified By NF-kappaB Deletion

CAMPESE, Antonio Francesco;GRAZIOLI, PAOLA;SCAFETTA, GAIA;NOCE, CLAUDIA;VERKHOVSKAIA, SOFIA;FELLI, MARIA PIA;GULINO, Alberto;SCREPANTI, Isabella
2012

Abstract

Background: The Notch3 deregulation inside T-cell compartment of transgenic (N3-tg) mice, induces an aggressive form of T-cell acute lymphoblastic leukemia (T-ALL), strongly sustained by an NF-κB constitutive activation, mainly represented by the p50/p65-dependent canonical pathway. To clarify the Notch/NF-κB relationships in the onset/progression of T-ALL, we decided to inhibit NF-κB canonical pathway in N3-tg mice. Methods: We generated N3-tg/p50-/- mice, deleted of the NF-κB/p50 subunit in a Notch3 transgenic background. The follow-up of N3-tg/p50-/- versus N3- tg mice was conducted and hematopoietic cell analysis was performed at different ages and in multiple tissues from the indicated animals by flow-cytometry techniques. Results: The p50 deletion inhibited the progression of T-ALL in N3-tg/p50-/- mice, as defined primarily by the peripheral expansion of immature CD4+CD8+ T cells. Surprisingly, the double mutant mice succumb earlier than N3-tg counterparts. Moribund N3-tg/p50-/- mice display the trait of a myeloproliferative disease, with the dramatic expansion of Mac1+Gr1+ myeloid cells in both spleen and blood, as well as of granulocyte/monocyte progenitors in the bone marrow. Preliminary data indicate that these cells do not express Notch3, suggesting that in the absence of p50 expression, Notch3 is able to mainly influence the equilibrium of the myeloid compartment in trans. Conclusions: The results presented suggest that the ablation of NF-κB canonical pathway may strongly impact on the outcomes of a T cell specific deregulation of Notch signaling. Thus, providing a useful experimental model to extend our understanding of Notch/NF-κB interplay and to unravel novel strategies for the therapy of different hematological malignancies.
2012
XXXI Congress of the Italian Society of Pathology and Translational Medicine
04 Pubblicazione in atti di convegno::04d Abstract in atti di convegno
The Outcome of Notch3-dependent T Cell Leukemia Is Modified By NF-kappaB Deletion / Campese, Antonio Francesco; Grazioli, Paola; Scafetta, Gaia; Noce, Claudia; Verkhovskaia, Sofia; C., Mari; Felli, MARIA PIA; Gulino, Alberto; Screpanti, Isabella. - In: THE AMERICAN JOURNAL OF PATHOLOGY. - ISSN 0002-9440. - ELETTRONICO. - 18:3 Suppl(2012), pp. 24-24. (Intervento presentato al convegno XXXI Congress of the Italian Society of Pathology and Translational Medicine tenutosi a Udine, Italia nel sep, 2012).
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/501906
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