Abstract
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-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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Antineoplastic Agents / pharmacology
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Bone Marrow / drug effects
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Bone Marrow / metabolism*
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Cell Line, Tumor
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Cell Proliferation / drug effects*
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Female
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Fusion Proteins, bcr-abl / metabolism
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Humans
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Hydroxamic Acids / pharmacology*
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MAP Kinase Signaling System / drug effects
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Male
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Middle Aged
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Myeloproliferative Disorders / drug therapy*
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Myeloproliferative Disorders / metabolism
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NF-kappa B / metabolism
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Nitriles
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Phosphatidylinositol 3-Kinases / metabolism*
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Protein Kinase Inhibitors / pharmacology
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Pyrazoles / pharmacology*
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Pyrimidines
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Signal Transduction / drug effects*
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Vorinostat
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Young Adult
Substances
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Antineoplastic Agents
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Hydroxamic Acids
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NF-kappa B
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Nitriles
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Protein Kinase Inhibitors
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Pyrazoles
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Pyrimidines
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Vorinostat
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ruxolitinib
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Fusion Proteins, bcr-abl
Grants and funding
This study was funded by research grants from "Instituto Português de Oncologia de Lisboa—Francisco Gentil" (IPOL-FG), "Associação Portuguesa Contra a Leucemia" (APCL) and "Liga Portuguesa Contra o Cancro" (LPCC). BAC is a recipient of a Post-Doc fellowship from "Fundação para a Ciência 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.