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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Publikace nespadá pod Lékařskou fakultu, ale pod Středoevropský technologický institut. Oficiální stránka publikace je na webu muni.cz.

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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

Rok publikování 2021
Druh Článek v odborném periodiku
Časopis / Zdroj haematologica
Fakulta / Pracoviště MU

Středoevropský technologický institut

Citace
www https://haematologica.org/article/view/9725
Doi http://dx.doi.org/10.3324/haematol.2019.238766
Klíčová slova SECRETASE INHIBITOR PF-03084014; ALK; TUMOR; EXPRESSION; NPM; GLYCOSYLATION; ADOLESCENTS; CRIZOTINIB; SIGNATURES; CHILDREN
Popis 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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