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Viral transduction of primary human lymphoma B cells reveals mechanisms_NatureCommunications.pdf (4.01 MB)

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2022-10-20

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cc by (c) Mangolini, M et al., 2022
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/206257

Viral transduction of primary human lymphoma B cells reveals mechanisms of NOTCH-mediated immune escape

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Recurs relacionat

https://doi.org/10.1038/s41467-022-33739-2

Resum

Hotspot mutations in the PEST-domain of NOTCH1 and NOTCH2 are recurrently identified in B cell malignancies. To address how NOTCH-mutations contribute to a dismal prognosis, we have generated isogenic primary human tumor cells from patients with Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL), differing only in their expression of the intracellular domain (ICD) of NOTCH1 or NOTCH2. Our data demonstrate that both NOTCH-paralogs facilitate immune-escape of malignant B cells by up-regulating PD-L1, partly dependent on autocrine interferon-? signaling. In addition, NOTCH-activation causes silencing of the entire HLA-class II locus via epigenetic regulation of the transcriptional co-activator CIITA. Notably, while NOTCH1 and NOTCH2 govern similar transcriptional programs, disease-specific differences in their expression levels can favor paralog-specific selection. Importantly, NOTCH-ICD also strongly down-regulates the expression of CD19, possibly limiting the effectiveness of immune-therapies. These NOTCH-mediated immune escape mechanisms are associated with the expansion of exhausted CD8+ T cells in vivo.© 2022. The Author(s).

Matèries

Epigènesi, Limfomes

Matèries (anglès)

Epigenesis, Lymphomas

Citació

Col·leccions

Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)

Citació

MANGOLINI, Maurizio, et al. Viral transduction of primary human lymphoma B cells reveals mechanisms of NOTCH-mediated immune escape. Nature Communications. 2022. Vol. 13, num. 6220. ISSN 2041-1723. [consulted: 6 of August of 2026]. Available at: https://hdl.handle.net/2445/206257

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