NOTCH1 drives immune-escape mechanisms in B cell malignancies

Mangolini, M.; Maiques-Diaz, A.; Charalampopoulou, S.; Gerhard-Hartmann, E.; Bloehdorn, J.; Moore, A.; Lu, J.; Roamio Franklin, V. N.; Chilamakuri, C. S.; Moutsoupoulos, I.; Rosenwald, A.; Stilgenbauer, S.; Zenz, T.; Mohorianu, I.; DSantos, C.; Deaglio, S.; Martin-Subero, J. I.; Ringshausen, I.

doi:10.1101/2021.04.10.439192

bioRxiv · 10.1101/2021.04.10.439192

NOTCH1 drives immune-escape mechanisms in B cell malignancies

Mangolini, M.·Maiques-Diaz, A.·Charalampopoulou, S.·Gerhard-Hartmann, E.·Bloehdorn, J.·Moore, A.·Lu, J.·Roamio Franklin, V. N.·Chilamakuri, C. S.·Moutsoupoulos, I.·Rosenwald, A.·Stilgenbauer, S.·Zenz, T.·Mohorianu, I.·DSantos, C.·Deaglio, S.·Martin-Subero, J. I.·Ringshausen, I.

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Abstract

NOTCH1 is a recurrently mutated gene in Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL). Functional studies to investigate its role have been hampered by the inability to genetically manipulate primary human lymphoma cells, attributed to low transduction-efficacy and procedure-associated toxicity. To overcome these limitations, we have developed a novel method to retrovirally transfer genes into malignant human B cells. We generated isogenic human tumor cells from patients with CLL and MCL, differing only in their expression of NOTCH1. Our data demonstrate that NOTCH1 facilitates immune-escape of malignant B cells by up-regulating PD-L1, partly dependent on autocrine interferon-{gamma} signaling. In addition, NOTCH1 causes silencing of the entire HLA-class II locus via suppression of the transcriptional co-activator CIITA. These NOTCH1-mediated immune escape mechanisms are associated with the expansion of CD4+ T cells in vivo, further contributing to the poor clinical outcome of NOTCH1-mutated CLL and MCL.

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Mangolini, M., Maiques-Diaz, A., Charalampopoulou, S., Gerhard-Hartmann, E., Bloehdorn, J., Moore, A., Lu, J., Roamio Franklin, V. N., Chilamakuri, C. S., Moutsoupoulos, I., Rosenwald, A., Stilgenbauer, S., Zenz, T., Mohorianu, I., DSantos, C., Deaglio, S., Martin-Subero, J. I., Ringshausen, I.. 2021-04-11. NOTCH1 drives immune-escape mechanisms in B cell malignancies. https://doi.org/10.1101/2021.04.10.439192

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