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.

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.

• Authors: Hugo Larose, Nina Prokoph, Jamie D Matthews, Michaela Schlederer, Sandra Högler, Ali F Alsulami, Stephen P Ducray, Edem Nuglozeh, Feroze M S Fazaludeen, Ahmed Elmouna, Monica Ceccon, Luca Mologni, Carlo Gambacorti-Passerini, Gerald Hoefler, Cosimo Lobello, Sarka Pospisilova, Andrea Janikova, Wilhelm Woessmann, Christine Damm-Welk, Martin Zimmermann, Alina Federova, Andrea Malone, Owen Smith, Mariusz Wasik, Giorgio Inghirami, Laurence Lamant, Tom L Blundell, Wolfram Klapper, Olaf Merkel, Amos G A Burke, Shahid Mian, Ibraheem Ashankyty, Lukas Kenner, Suzanne D Turner
• Journal: Haematologica (Haematologica) Vol. 106 Issue 6 Pg. 1693-1704 (06 01 2021) ISSN: 1592-8721 [Electronic] Italy
• PMID: 32327503 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• NOTCH1 protein, human
• Receptor, Notch1
• Protein-Tyrosine Kinases
• Receptor Protein-Tyrosine Kinases

Topics

• Cell Line, Tumor
• Humans
• Lymphoma, Large-Cell, Anaplastic (drug therapy, genetics)
• Mutation
• Neoplasm Recurrence, Local
• Protein-Tyrosine Kinases (genetics)
• Receptor Protein-Tyrosine Kinases (genetics)
• Receptor, Notch1 (genetics)
• Exome Sequencing