Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038002 (splenomegaly)
 9,873 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ruxolitinib, formerly known as INCB018424 or INC424, is a potent and selective oral inhibitor of JAK1 and JAK2. Ruxolitinib has been approved for the treatment of myelofibrosis, which is characterized, biologically, by the activation of the JAK-STAT pathway and, clinically, by bone marrow fibrosis, splenomegaly, abnormal blood counts, and poor quality-of-life through associated symptoms. Ruxolitinib treatment results in a meaningful reduction in spleen size and symptom burden in the majority of myelofibrosis patients, and it may also have a favorable effect on survival. Treatment response apparently does not depend on the presence of a JAK2 V617F mutation. The predominant toxicities are thrombocytopenia and anemia. The metabolization of ruxolitinib through CYP3A4 needs to be considered particularly if co-administered with potent CYP3A4 inhibitors. Several further JAK inhibitors are currently studied in myelofibrosis or other immuno-inflammatory diseases.
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PMID:Ruxolitinib. 2475 98

Ruxolitinib, formerly known as INCB018424 or INC424, is a potent and selective oral inhibitor of Janus kinase (JAK) 1 and JAK2. Ruxolitinib has been approved for the treatment of myelofibrosis (MF) by the US Food and Drug Administration (FDA) in 2011 and by the European Medicines Agency (EMA) in 2012, followed by the approval for the treatment of hydroxyurea (HU)-resistant or -intolerant polycythemia vera (PV) in 2014. Both MF and PV are myeloproliferative neoplasms (MPNs) which are characterized by the aberrant activation of the JAK-STAT pathway. Clinically, MF features bone marrow fibrosis, splenomegaly, abnormal blood counts, and poor quality-of-life through associated symptoms. PV is characterized by the overproduction of primarily red blood cells (RBC), risk of thrombotic complications, and development of secondary MF. Ruxolitinib treatment results in a meaningful reduction in spleen size and symptom burden in the majority of MF patients and may also have a favorable effect on survival. In PV, ruxolitinib effectively controls the hematocrit and reduces splenomegaly. Since recently, ruxolitinib is also under investigation for the treatment of graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Toxicities of ruxolitinib include myelosuppression, which results in dose-limiting thrombocytopenia and anemia, and viral reactivations. The metabolization of ruxolitinib through CYP3A4 needs to be considered particularly if co-administered with potent CYP3A4 inhibitors. Several further JAK inhibitors are currently under investigation for MPNs or other immuno-inflammatory diseases.
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PMID:Ruxolitinib. 3006 28

Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by cytopenia and extramedullary hematopoiesis, resulting in splenomegaly. Multiple pathological mechanisms (e.g., circulating cytokines and genetic alterations, such as JAKV617F mutation) have been implicated in the etiology of MF, but the molecular mechanism causing resistance to JAK2V617F inhibitor therapy remains unknown. Among MF patients who were treated with the JAK inhibitor ruxolitinib, we compared noncoding RNA profiles of ruxolitinib therapy responders versus nonresponders and found miR-543 was significantly upregulated in nonresponders. We validated these findings by reverse transcription-quantitative PCR. in this same cohort, in 2 additional independent MF patient cohorts from the United States and Romania, and in a JAK2V617F mouse model of MF. Both in vitro and in vivo models were used to determine the underlying molecular mechanism of miR-543 in MF. Here, we demonstrate that miR-543 targets the dioxygenases ten-eleven translocation 1 (TET1) and 2 (TET2) in patients and in vitro, causing increased levels of global 5-methylcytosine, while decreasing the acetylation of histone 3, STAT3, and tumor protein p53. Mechanistically, we found that activation of STAT3 by JAKs epigenetically controls miR-543 expression via binding the promoter region of miR-543. Furthermore, miR-543 upregulation promotes the expression of genes related to drug metabolism, including CYP3A4, which is involved in ruxolitinib metabolism. Our findings suggest miR-543 as a potentially novel biomarker for the prognosis of MF patients with a high risk of treatment resistance and as a potentially new target for the development of new treatment options.
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PMID:miR-543 regulates the epigenetic landscape of myelofibrosis by targeting TET1 and TET2. 3194 38