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