| Autor: |
Giulia Pianigiani, Andrea Gagliardi, Federica Mezzasoma, Francesca Rocchio, Valentina Tini, Barbara Bigerna, Paolo Sportoletti, Simona Caruso, Andrea Marra, Sara Peruzzi, Eleonora Petito, Giulio Spinozzi, Sharon Shacham, Yosef Landesman, Concetta Quintarelli, Paolo Gresele, Franco Locatelli, Maria Paola Martelli, Brunangelo Falini, Lorenzo Brunetti |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Blood advances. 6(22) |
| ISSN: |
2473-9537 |
| Popis: |
NPM1 is the most frequently mutated gene in adults with acute myeloid leukemia (AML). The interaction between mutant NPM1 (NPM1c) and exportin-1 (XPO1) causes aberrant cytoplasmic dislocation of NPM1c and promotes the high expression of homeobox (HOX) genes, which is critical for maintaining the leukemic state of NPM1-mutated cells. Although there is a rationale for using XPO1 inhibitors in NPM1-mutated AML, selinexor administered once or twice per week did not translate into clinical benefit in patients with NPM1 mutations. Here, we show that this dosing strategy results in only a temporary disruption of the XPO1-NPM1c interaction, limiting the efficacy of selinexor. Because the second-generation XPO1 inhibitor eltanexor can be administered more frequently, we tested the antileukemic activity of prolonged XPO1 inhibition in NPM1-mutated AML models. Eltanexor caused irreversible HOX downregulation, induced terminal AML differentiation, and prolonged the survival of leukemic mice. This study provides essential information for the appropriate design of clinical trials with XPO1 inhibitors in NPM1-mutated AML. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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