The bone marrow-mediated protection of myeloproliferative neoplastic cells to vorinostat and ruxolitinib relies on the activation of JNK and PI3K Signalling Pathways

Bruno A. Cardoso, Hélio Belo, João T. Barata, António M. Almeida

Resultado de pesquisarevisão de pares

11 Citações (Scopus)

Resumo

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, MEKERK and NF-κB. 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.
Idioma originalEnglish
Número do artigoe0143897
RevistaPLoS ONE
Volume10
Número de emissão12
DOIs
Estado da publicaçãoPublicado - 1 dez 2015
Publicado externamenteSim

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