| Literature DB >> 36266281 |
Maurizio Mangolini1,2, Alba Maiques-Diaz3, Stella Charalampopoulou3, Elena Gerhard-Hartmann4, Johannes Bloehdorn5, Andrew Moore1,2, Giorgia Giachetti1,2, Junyan Lu6,7, Valar Nila Roamio Franklin8, Chandra Sekkar Reddy Chilamakuri8, Ilias Moutsopoulos1, Andreas Rosenwald4, Stephan Stilgenbauer5, Thorsten Zenz9,10, Irina Mohorianu1, Clive D'Santos8, Silvia Deaglio11, Daniel J Hodson1,2, Jose I Martin-Subero3,12, Ingo Ringshausen13,14.
Abstract
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-γ 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.Entities:
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Year: 2022 PMID： 36266281 PMCID： PMC9585083 DOI： 10.1038/s41467-022-33739-2
Source DB: PubMed Journal: Nat Commun ISSN： 2041-1723 Impact factor: 17.694