Abstract:Myelofibrosis (MF) and polycythemia vera (PV) are BCR-ABL1-negative myeloproliferative neoplasms associated with somatic hematopoietic stem cell mutations leading to over activation of JAK–STAT signaling. MF and PV are pathogenically related and share specific clinical features such as splenomegaly and constitutional symptoms. The MF phenotype is dominated by the effects of progressive bone marrow fibrosis resulting in shortened survival. In contrast, elevated thrombosis risk due to erythrocytosis is the prima… Show more
“…Ruxolitinib is FDA-approved for the treatment of myelofibrosis and was previously shown to efficiently block pro-inflammatory cytokine release from T cells in vivo in the context of myelofibrosis [31]. Ruxolitinib has favorable pharmacokinetics and a well-characterized in vivo safety profile [33], and therefore represented a promising candidate to attenuate ingenol-induced pro-inflammatory cytokine induction.Fig. 2Kinase inhibitor screening identifies compounds that attenuate ingenol-induced cytokine release.…”
BackgroundDespite the durable viral suppression afforded by antiretroviral therapy, HIV-1 eradication will require strategies to target latently infected cells that persist in infected individuals. Protein kinase C (PKC) activation is a promising strategy to reactivate latent proviruses and allow for subsequent recognition and clearance of infected cells by the immune system. Ingenol derivatives are PKC agonists that induce latency reversal but also lead to T cell activation and the release of pro-inflammatory cytokines, which would be undesirable in vivo. In this work, we sought to identify compounds that would suppress pro-inflammatory cytokine production in the context of PKC activation.Design and methodsWe performed an in vitro screen to identify compounds that could dampen pro-inflammatory cytokine release associated with T cell activation, using IL-6 as a model cytokine. We then tested the ability of the most promising screening hit, the FDA-approved Janus Kinase (JAK) inhibitor ruxolitinib, to diminish release of multiple cytokines and its effect on latency reversal using cells from HIV-1-positive, aviremic participants.ResultsWe demonstrate that co-administration of ruxolitinib with ingenol-3,20-dibenzoate significantly reduces pro-inflammatory cytokine release without impairing latency reversal ex vivo.ConclusionThe combination of ingenol compounds and JAK inhibition represents a novel strategy for HIV-1 eradication.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-016-0319-0) contains supplementary material, which is available to authorized users.
“…Ruxolitinib is FDA-approved for the treatment of myelofibrosis and was previously shown to efficiently block pro-inflammatory cytokine release from T cells in vivo in the context of myelofibrosis [31]. Ruxolitinib has favorable pharmacokinetics and a well-characterized in vivo safety profile [33], and therefore represented a promising candidate to attenuate ingenol-induced pro-inflammatory cytokine induction.Fig. 2Kinase inhibitor screening identifies compounds that attenuate ingenol-induced cytokine release.…”
BackgroundDespite the durable viral suppression afforded by antiretroviral therapy, HIV-1 eradication will require strategies to target latently infected cells that persist in infected individuals. Protein kinase C (PKC) activation is a promising strategy to reactivate latent proviruses and allow for subsequent recognition and clearance of infected cells by the immune system. Ingenol derivatives are PKC agonists that induce latency reversal but also lead to T cell activation and the release of pro-inflammatory cytokines, which would be undesirable in vivo. In this work, we sought to identify compounds that would suppress pro-inflammatory cytokine production in the context of PKC activation.Design and methodsWe performed an in vitro screen to identify compounds that could dampen pro-inflammatory cytokine release associated with T cell activation, using IL-6 as a model cytokine. We then tested the ability of the most promising screening hit, the FDA-approved Janus Kinase (JAK) inhibitor ruxolitinib, to diminish release of multiple cytokines and its effect on latency reversal using cells from HIV-1-positive, aviremic participants.ResultsWe demonstrate that co-administration of ruxolitinib with ingenol-3,20-dibenzoate significantly reduces pro-inflammatory cytokine release without impairing latency reversal ex vivo.ConclusionThe combination of ingenol compounds and JAK inhibition represents a novel strategy for HIV-1 eradication.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-016-0319-0) contains supplementary material, which is available to authorized users.
“…48 But there are, to our knowledge, no data that bear directly on the pathway’s relationship to proteinaceous aggregate accumulation or clearance. Using the human chronic myeloid leukemia cell line K-562, an association between ruxolitinib treatment and enhanced autophagy as determined by LC3B-II puncta formation was recently documented.…”
Rationale
Post-mitotic cells such as cardiomyocytes appear to be particularly susceptible to proteotoxic stimuli, and large, proteinaceous deposits are characteristic of the Desmin Related Cardiomyopathies and crystallin cardiomyopathic diseases. Increased activity of protein clearance pathways in the cardiomyocyte such as proteasomal degradation and autophagy have proven to be beneficial in maintaining cellular and cardiac function in the face of multiple proteotoxic insults, holding open the possibility of targeting these processes for the development of effective therapeutics.
Objective
Here we undertake an unbiased, total genome screen for RNA transcripts and their protein products that impact on aggregate accumulations in the cardiomyocytes.
Methods and Results
Primary mouse cardiomyocytes that accumulate aggregates as a result of a mutant αB crystallin causative for human Desmin Related Cardiomyopathy were used for a total genome-wide screen to identify gene products that impacted on aggregate formation. We infected cardiomyocytes using a short hairpin RNA lentivirus library in which the mouse genome was represented. The screen identified multiple candidates in a number of cell signaling pathways that were able to mediate significant decreases in aggregate levels.
Conclusions
Subsequent validation of one of these candidates, Janus kinase 1 (Jak1), a tyrosine kinase of the non-receptor type, confirmed the usefulness of this approach in identifying previously unsuspected players in proteotoxic processes.
“…The drug is approved by the US Food and Drug Administration for treatment of adult PV patients with an inadequate response to/or intolerant of hydroxycarbamide, after the demonstration of clinical benefit in phase II and III studies,26 27 particularly in patients with persisting splenomegaly 28. Anaemia and thrombocytopaenia were the most common haematological adverse events associated with ruxolitinib,26 requiring dose reduction or interruption of treatment.…”
Budd-Chiari syndrome (BCS) is caused by hepatic venous outflow obstruction commonly seen with myeloproliferative neoplasms (MPNs). Polycythaemia vera (PV) is a very rare MPN in childhood. This is the youngest reported patient diagnosed with PV and BCS secondary to mutation.A 26-month-old girl was admitted with a 5-month history of abdominal distension, hepatosplenomegaly and ascites. Imaging studies revealed occlusion of the right hepatic vein and marked attenuation of the middle and left hepatic veins. BCS was diagnosed after excluding other causes of chronic liver disease. Mandatory prothrombotic workup revealed underlying PV.Partial recanalisation of hepatic veins occurred following anticoagulation therapy and PV was well controlled by pegylated interferon and hydroxycarbamide until she developed nephrotic syndrome, likely secondary to pegylated interferon. Therefore, treatment was modified to ruxolitinib, a novel-JAK-2 inhibitor; the therapy has been effective for almost 20 months with a good response and has no side effects.
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