RESUMEN
Chronic inflammation is frequently associated with myeloproliferative neoplasms (MPN), but the role of inflammation in the pathogenesis of MPN remains unclear. Expression of the proinflammatory cytokine interleukin-1 (IL-1) is elevated in patients with MPN as well as in Jak2V617F knock-in mice. Here, we show that genetic deletion of IL-1 receptor 1 (IL-1R1) normalizes peripheral blood counts, reduces splenomegaly and ameliorates bone marrow fibrosis in homozygous Jak2V617F mouse model of myelofibrosis. Deletion of IL-1R1 also significantly reduces Jak2V617F mutant hematopoietic stem/progenitor cells. Exogenous administration of IL-1ß enhances myeloid cell expansion and accelerates the development of bone marrow fibrosis in heterozygous Jak2V617F mice. Furthermore, treatment with anti-IL-1R1 antibodies significantly reduces leukocytosis and splenomegaly, and ameliorates bone marrow fibrosis in homozygous Jak2V617F mice. Collectively, these results suggest that IL-1 signaling plays a pathogenic role in MPN disease progression, and targeting of IL-1R1 could be a useful strategy for the treatment of myelofibrosis.
Asunto(s)
Janus Quinasa 2/metabolismo , Trastornos Mieloproliferativos , Neoplasias , Mielofibrosis Primaria , Animales , Inflamación/genética , Interleucina-1 , Janus Quinasa 2/genética , Ratones , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/patología , Mielofibrosis Primaria/genética , Receptores Tipo I de Interleucina-1/metabolismo , Esplenomegalia/genéticaRESUMEN
Myelofibrosis (MF) is the deadliest form of myeloproliferative neoplasm (MPN). The JAK inhibitor Ruxolitinib can reduce constitutional symptoms but it does not substantially improve bone marrow fibrosis. Pim1 expression is significantly elevated in MPN/MF hematopoietic progenitors. Here, we show that genetic ablation of Pim1 blocked the development of myelofibrosis induced by Jak2V617F and MPLW515L. Pharmacologic inhibition of Pim1 with a second-generation Pim kinase inhibitor TP-3654 significantly reduced leukocytosis and splenomegaly, and attenuated bone marrow fibrosis in Jak2V617F and MPLW515L mouse models of MF. Combined treatment of TP-3654 and Ruxolitinib resulted in greater reduction of spleen size, normalization of blood leukocyte counts and abrogation of bone marrow fibrosis in murine models of MF. TP-3654 treatment also preferentially inhibited Jak2V617F mutant hematopoietic progenitors in mice. Mechanistically, we show that TP-3654 treatment significantly inhibits mTORC1, MYC and TGF-ß signaling in Jak2V617F mutant hematopoietic cells and diminishes the expression of fibrotic markers in the bone marrow. Collectively, our results suggest that Pim1 plays an important role in the pathogenesis of MF, and inhibition of Pim1 with TP-3654 might be useful for treatment of MF.
Asunto(s)
Mielofibrosis Primaria/tratamiento farmacológico , Mielofibrosis Primaria/genética , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-pim-1/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-pim-1/genética , Animales , Línea Celular , Modelos Animales de Enfermedad , Eliminación de Gen , Humanos , Janus Quinasa 2/genética , Ratones , Ratones Noqueados , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
INTRODUCTION: Adhesive small bowel obstruction (ASBO) has classically been managed with nasogastric tube decompression and watchful waiting. Our group developed an evidence-based protocol to manage ASBO utilizing a water-soluble contrast (WSC) agent. We hypothesized the protocol would decrease the length of stay (LOS) for patients admitted with ASBO along with the time interval from admission to surgery. METHOD: From 2010 to 2018, a retrospective review was performed, including all patients admitted with a diagnosis of ASBO. These patients were divided into two groups: the preprotocol group included years 2010-2013 and the postprotocol group included years 2015-2018. A Student t-test and a two-proportion z-test were used for statistical analysis. RESULT: We captured 767 patients; 296 in the preprotocol group and 471 in the postprotocol group. We found a significant decrease in overall LOS between the preprotocol and postprotocol groups (6.56 d versus 4.08 d; P < 0.001) along with decreases in LOS for patients managed nonoperatively (5.36 d versus 3.42 d; P < 0.001) and operatively (16.09 d versus 9.47 d; P < 0.001). Time interval from admission to the operation was significantly decreased in the postprotocol group (3.79 d versus 2.10 d; P < 0.050). We identified a trend toward decreased rates of bowel ischemia and resections with our protocol. CONCLUSIONS: These results reaffirm previous reports of WSC's impact on overall LOS in ASBO while showing a similar impact on both operative and nonoperative groups. The decreased time interval between admission and operation may impact the incidence of bowel ischemia and resections.