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

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Authors

LAROSE H. PROKOPH N. MATTHEWS J.D. SCHLEDERER M. HOGLER S. ALSULAMI A.F. DUCRAY S.P. NUGLOZEH E. FAZALUDEEN M.F. ELMOUNA A. CECCON M. MOLOGNI L. GAMBACORTI-PASSERINI C. HOEFLER G. LOBELLO Cosimo POSPÍŠILOVÁ Šárka JANIKOVA A. WOESSMANN W. DAMM-WELK C. ZIMMERMANN M. FEDOROVA A. MALONE A. SMITH O. WASIK M. INGHIRAMI G. LAMANT L. BLUNDELL T.L. KLAPPER W. MERKEL O. BURKE G.A.A. MIAN S. ASHANKYTY I. KENNER L. TURNER Suzanne Dawn

Year of publication 2021
Type Article in Periodical
Magazine / Source haematologica
MU Faculty or unit

Central European Institute of Technology

Citation
Web https://haematologica.org/article/view/9725
Doi http://dx.doi.org/10.3324/haematol.2019.238766
Keywords SECRETASE INHIBITOR PF-03084014; ALK; TUMOR; EXPRESSION; NPM; GLYCOSYLATION; ADOLESCENTS; CRIZOTINIB; SIGNATURES; CHILDREN
Description 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, we performed whole-exome sequencing of anaplastic lymphoma kinase (ALK)(+) ALCL, as well as gene-set enrichment analysis. This revealed that the T-cell receptor 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 patients' samples. Furthermore, we demonstrated that NPM-ALK promotes NOTCH1 expression through binding of STAT3 upstream of NOTCH1. Moreover, inhibition of NOTCH1 with gamma-secretase inhibitors or silencing by short hairpin RNA leads to apoptosis; co-treatment in vitro with the ALK inhibitor crizotinib led to additive/synergistic antitumor activity suggesting that 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 gamma-secretase inhibitors. 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.
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