RESUMO
Acute myeloid leukemia (AML) is sustained by small populations of leukemia stem cells (LSCs) that can resist available treatments and represent important barriers to cure. Although previous studies have shown increased signal transducer and activator of transcription (STAT)3 and STAT5 phosphorylation in AML leukemic blasts, the role of Janus kinase (JAK) signaling in primary AML compared with normal stem cells has not been directly evaluated. We show here that JAK/STAT signaling is increased in LSCs, particularly from high-risk AML. JAK2 inhibition using small molecule inhibitors or interference RNA reduced growth of AML LSCs while sparing normal stem cells both in vitro and in vivo. Increased JAK/STAT activity was associated with increased expression and altered signaling through growth factor receptors in AML LSCs, including receptor tyrosine kinase c-KIT and FMS-related tyrosine kinase 3 (FLT3). Inhibition of c-KIT and FLT3 expression significantly inhibited JAK/STAT signaling in AML LSCs, and JAK inhibitors effectively inhibited FLT3-mutated AML LSCs. Our results indicate that JAK/STAT signaling represents an important signaling mechanism supporting AML LSC growth and survival. These studies support continued evaluation of strategies for JAK/STAT inhibition for therapeutic targeting of AML LSCs.
Assuntos
Janus Quinase 2/metabolismo , Leucemia Mieloide Aguda/metabolismo , Células-Tronco Neoplásicas/metabolismo , Receptores de Fatores de Crescimento/metabolismo , Transdução de Sinais , Animais , Antígenos CD34/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Modelos Animais de Doenças , Feminino , Regulação Leucêmica da Expressão Gênica , Humanos , Janus Quinase 2/antagonistas & inibidores , Janus Quinases/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Camundongos , Células-Tronco Neoplásicas/efeitos dos fármacos , Fenótipo , Fosforilação , Pirazóis/farmacologia , Pirimidinas/farmacologia , Interferência de RNA , Receptores de Fatores de Crescimento/genética , Fatores de Transcrição STAT/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Ecosystems of Florida Everglades are highly sensitive to phosphorus loading. Future restoration efforts, which focus on restoring Everglades water flows, may pose a threat to the health of these ecosystems. To determine the fate and transport of total phosphorus and evaluate proposed Everglades restoration, a water quality model has been developed using the hydrodynamic results from the M3ENP (Mike Marsh Model of Everglades National Park)--a physically-based hydrological numerical model which uses MIKE SHE/MIKE 11 software. Using advection-dispersion with reactive transport for the model, parameters were optimized and phosphorus loading in the overland water column was modeled with good accuracy (60%). The calibrated M3ENP-AD model was then modified to include future bridge construction and canal water level changes, which have shown to increase flows into ENP. These bridge additions increased total dissolved phosphorus (TP) load downstream in Shark Slough and decreased TP load in downstream Taylor Slough. However, there was a general decrease in TP concentration and TP mass per area over the entire model domain. The M3ENP-AD model has determined the mechanisms for TP transport and quantified the impacts of ENP restoration efforts on the spatial-temporal distribution of phosphorus transport. This tool can be used to guide future Everglades restoration decisions.