Characterization of activating mutations of NOTCH3 in T cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies

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Characterization of activating mutations of NOTCH3 in T cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies

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Title: Characterization of activating mutations of NOTCH3 in T cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies
Author: Bernasconi-Elias, Paula; Hu, Tiancen; Jenkins, David; Firestone, Brant; Gans, Sara; Kurth, Esther; Capodieci, Paola; Deplazes-Lauber, Joelle; Petropoulos, Konstantin; Thiel, Phillip; Ponsel, Dirk; Choi, Sung Hee; LeMotte, Peter; London, Anne; Goetcshkes, Margaret; Nolin, Erin; Jones, Michael D.; Slocum, Kelly; Kluk, Michael J.; Weinstock, David M.; Christodoulou, Alexandra; Weinberg, Olga; Jaehrling, Jan; Ettenberg, Seth A.; Buckler, Alan; Blacklow, Stephen C.; Aster, Jon C.; Fryer, Christy J.

Note: Order does not necessarily reflect citation order of authors.

Citation: Bernasconi-Elias, P., T. Hu, D. Jenkins, B. Firestone, S. Gans, E. Kurth, P. Capodieci, et al. 2016. “Characterization of activating mutations of NOTCH3 in T cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies.” Oncogene 35 (47): 6077-6086. doi:10.1038/onc.2016.133. http://dx.doi.org/10.1038/onc.2016.133.
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Abstract: Notch receptors have been implicated as oncogenic drivers in several cancers, the most notable example being NOTCH1 in T-cell acute lymphoblastic leukemia (T-ALL). To characterize the role of activated NOTCH3 in cancer, we generated an antibody that detects the neo-epitope created upon gamma-secretase cleavage of NOTCH3 to release its intracellular domain (ICD3), and sequenced the negative regulatory region (NRR) and PEST domain coding regions of NOTCH3 in a panel of cell lines. We also characterize NOTCH3 tumor-associated mutations that result in activation of signaling and report new inhibitory antibodies. We determined the structural basis for receptor inhibition by obtaining the first co-crystal structure of a NOTCH3 antibody with the NRR protein and defined two distinct epitopes for NRR antibodies. The antibodies exhibit potent anti-leukemic activity in cell lines and tumor xenografts harboring NOTCH3 activating mutations. Screening of primary T-ALL samples reveals that two of 40 tumors examined show active NOTCH3 signaling. We also identified evidence of NOTCH3 activation in 12 of 24 patient-derived orthotopic xenograft models, two of which exhibit activation of NOTCH3 without activation of NOTCH1. Our studies provide additional insights into NOTCH3 activation and offer a path forward for identification of cancers that are likely to respond to therapy with NOTCH3 selective inhibitory antibodies.
Published Version: doi:10.1038/onc.2016.133
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5102827/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:29625977
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