Biological Effects of BET Inhibition by OTX015 (MK-8628) and JQ1 in NPM1-Mutated (NPM1c) Acute Myeloid Leukemia (AML)
BET inhibitors (BETi) including OTX015 (MK-8628) and JQ1 demonstrated antileukemic activity including <i>NPM1c</i> AML cells. Nevertheless, the biological consequences of BETi in <i>NPM1c</i> AML were not fully investigated. Even if of better prognosis AML patients with <i...
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| Autores principales: | , , , , , , , , , , , , , , , , , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
MDPI AG
2021
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/52d5e94b12ce456bbf18b65e4c1fbdfe |
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| Sumario: | BET inhibitors (BETi) including OTX015 (MK-8628) and JQ1 demonstrated antileukemic activity including <i>NPM1c</i> AML cells. Nevertheless, the biological consequences of BETi in <i>NPM1c</i> AML were not fully investigated. Even if of better prognosis AML patients with <i>NPM1c</i> may relapse and treatment remains difficult. Differentiation-based therapy by all trans retinoic acid (ATRA) combined with arsenic trioxide (ATO) demonstrated activity in <i>NPM1c</i> AML. We found that BETi, similar to ATO + ATRA, induced differentiation and apoptosis which was <i>TP53</i> independent in the <i>NPM1c</i> cell line OCI-AML3 and primary cells. Furthermore, BETi induced proteasome-dependent degradation of NPM1c. BETi degraded NPM1c in the cytosol while BRD4 is degraded in the nucleus which suggests that restoration of the NPM1/BRD4 equilibrium in the nucleus of <i>NPM1c</i> cells is essential for the efficacy of BETi. While ATO + ATRA had significant biological activity in <i>NPM1c</i> IMS-M2 cell line, those cells were resistant to BETi. Gene profiling revealed that IMS-M2 cells probably resist to BETi by upregulation of LSC pathways independently of the downregulation of a core BET-responsive transcriptional program. ATO + ATRA downregulated a <i>NPM1c</i> specific <i>HOX</i> gene signature while anti-leukemic effects of BETi appear <i>HOX</i> gene independent. Our preclinical results encourage clinical testing of BETi in <i>NPM1c</i> AML patients. |
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