A carregar...
Publicação
The bone marrow-mediated protection of myeloproliferative neoplastic cells to Vorinostat and Ruxolitinib relies on the activation of JNK and PI3K signalling pathways
| Nome: | Descrição: | Tamanho: | Formato: | |
|---|---|---|---|---|
| 2.89 MB | Adobe PDF |
Orientador(es)
Resumo(s)
The classical BCR-ABL-negative Myeloproliferative Neoplasms (MPN) are a group of heterogeneous haematological diseases characterized by constitutive JAK-STAT pathway activation. Targeted therapy with Ruxolitinib, a JAK1/2-specific inhibitor, achieves symptomatic improvement but does not eliminate the neoplastic clone. Similar effects are seen with histone deacetylase inhibitors (HDACi), albeit with poorer tolerance. Here, we show that bone marrow (BM) stromal cells (HS-5) protected MPN-derived cell lines (SET-2; HEL and UKE-1) and MPN patient-derived BM cells from the cytotoxic effects of Ruxolitinib and the HDACi Vorinostat. This protective effect was mediated, at least in part, by the secretion of soluble factors from the BM stroma. In addition, it correlated with the activation of signalling pathways important for cellular homeostasis, such as JAK-STAT, PI3K, JNK, MEK-ERK and NF-kappa B. Importantly, the pharmacological inhibition of JNK and PI3K pathways completely abrogated the BM protective effect on MPN cell lines and MPN patient samples. Our findings shed light on mechanisms of tumour survival and may indicate novel therapeutic approaches for the treatment of MPN.
Descrição
This study was funded by research grants from "Instituto Portugues de Oncologia de Lisboa-Francisco Gentil" (IPOL-FG), "Associacao Portuguesa Contra a Leucemia" (APCL) and "Liga Portuguesa Contra o Cancro" (LPCC). BAC is a recipient of a Post-Doc fellowship from "Fundacao para a Ciencia e Tecnologia" (FCT-SFRH/BPD/79209/2011) and HB from LPCC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Palavras-chave
HISTONE-DEACETYLASE INHIBITOR POLYCYTHEMIA-VERA PRIMARY MYELOFIBROSIS MUTATION ESSENTIAL THROMBOCYTHEMIA ACUTE LYMPHOBLASTIC-LEUKEMIA TYROSINE KINASE JAK2 STEM-CELL PHASE-II PROGENITOR CELLS Multidisciplinary Sciences