BIRC3 Expression Predicts CLL Progression and Defines Treatment Sensitivity via Enhanced NF-κB Nuclear Translocation.
Clin Cancer Res
; 25(6): 1901-1912, 2019 03 15.
Article
em En
| MEDLINE
| ID: mdl-30487125
ABSTRACT
PURPOSE:
Chronic lymphocytic leukemia (CLL) pathophysiology is characterized by a complex crosstalk of tumor cells with the microenvironment. In this regard, NF-κB signaling is considered as important signaling axis, with a variety of key molecules aberrantly expressed or genetically altered in patients with CLL. One of these molecules is BIRC3 (cIAP2), a central regulator of noncanonical NF-κB signaling that serves as pathway brake in the absence of microenvironmental signals. However, the contribution of BIRC3 expression to CLL progression and potential therapeutic implications is unknown.ExperimentalDesign:
We analyzed the role of BIRC3 mRNA expression in primary CLL samples in correlation to clinical datasets and used ex vivo assays to investigate functional consequences on the level of NF-κB signaling and downstream target gene regulation. For proof-of-principle experiments, we used genetically modified cell lines.RESULTS:
We demonstrate that patients with CLL with low BIRC3 expression experience a more rapid disease progression, which coincides with an enhanced activation of canonical NF-κB target genes evidenced by an increased p65/Rel-B nuclear translocation ratio. As a consequence of enhanced canonical NF-κB target gene activation, both anti- and proapoptotic Bcl-2 family members were upregulated in BIRC3low primary CLL cells, which was associated with higher sensitivity to venetoclax treatment in vitro.CONCLUSIONS:
Here we show the impact of BIRC3 expression in CLL disease progression in the absence of BIRC3 mutations and show altered canonical NF-κB target gene activation with therapeutic implications.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Sulfonamidas
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Leucemia Linfocítica Crônica de Células B
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NF-kappa B
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Resistencia a Medicamentos Antineoplásicos
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Compostos Bicíclicos Heterocíclicos com Pontes
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Proteína 3 com Repetições IAP de Baculovírus
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Áustria