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Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Larose, H; Prokoph, N; Matthews, JD; Schlederer, M; Högler, S; Alsulami, AF; Ducray, SP; Nuglozeh, E; Fazaludeen, FMS; Elmouna, A; Ceccon, M; Mologni, L; Gambacorti-Passerini, C; Hoefler, G; Lobello, C; Pospisilova, S; Janikova, A; Woessmann, W; Damm-Welk, C; Zimmermann, M; Federova, A; Malone, A; Smith, O; Wasik, M; Inghirami, G; Lamant, L; Blundell, TL; Klapper, W; Merkel, O; Burke, AGA; Mian, S; Ashankyty, I; Kenner, L; Turner, SD.
Whole Exome Sequencing reveals NOTCH1 mutations in anaplastic large cell lymphoma and points to Notch both as a key pathway and a potential therapeutic target.
HAEMATOLOGICA. 2021; 106(6): 1693-1704.
Doi: 10.3324/haematol.2019.238766
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- Co-authors Med Uni Graz
- Höfler Gerald
- Kenner Lukas
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- Abstract:
- Patients diagnosed with Anaplastic Large Cell Lymphoma (ALCL) are still treated with toxic multi-agent chemotherapy and as many as 25-50% of patients relapse. To understand disease pathology and to uncover novel targets for therapy, Whole-Exome Sequencing (WES) of Anaplastic Lymphoma Kinase (ALK)+ ALCL was performed as well as Gene-Set Enrichment Analysis. This revealed that the T-cell receptor (TCR) and Notch pathways were the most enriched in mutations. In particular, variant T349P of NOTCH1, which confers a growth advantage to cells in which it is expressed, was detected in 12% of ALK+ and ALK- ALCL patient samples. Furthermore, we demonstrate that NPM-ALK promotes NOTCH1 expression through binding of STAT3 upstream of NOTCH1. Moreover, inhibition of NOTCH1 with γ-secretase inhibitors (GSIs) or silencing by shRNA leads to apoptosis; co-treatment in vitro with the ALK inhibitor Crizotinib led to additive/synergistic anti-tumour activity suggesting this may be an appropriate combination therapy for future use in the circumvention of ALK inhibitor resistance. Indeed, Crizotinib-resistant and sensitive ALCL were equally sensitive to GSIs. In conclusion, we show a variant in the extracellular domain of NOTCH1 that provides a growth advantage to cells and confirm the suitability of the Notch pathway as a second-line druggable target in ALK+ ALCL.
- Find related publications in this database (using NLM MeSH Indexing)
- Cell Line, Tumor - administration & dosage
- Humans - administration & dosage
- Lymphoma, Large-Cell, Anaplastic - drug therapy, genetics
- Mutation - administration & dosage
- Neoplasm Recurrence, Local - administration & dosage
- Protein-Tyrosine Kinases - genetics
- Receptor Protein-Tyrosine Kinases - genetics
- Receptor, Notch1 - genetics
- Whole Exome Sequencing - administration & dosage