|Title||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.|
|Publication Type||Journal Article|
|Year of Publication||2021|
|Authors||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|
|Date Published||2021 06 01|
|Keywords||Cell Line, Tumor, Humans, Lymphoma, Large-Cell, Anaplastic, Mutation, Neoplasm Recurrence, Local, Protein-Tyrosine Kinases, Receptor Protein-Tyrosine Kinases, Receptor, Notch1, Whole Exome Sequencing|
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.
|PubMed Central ID||PMC8168516|
|Grant List||P01 CA229100 / CA / NCI NIH HHS / United States|
Giorgio Inghirami, M.D.