RESUMEN
Internal tandem duplication in Fms-like tyrosine kinase 3 (FLT3-ITD) is the most frequent mutation observed in acute myeloid leukemia (AML) and correlates with poor prognosis. FLT3 tyrosine kinase inhibitors are promising for targeted therapy. Here, we investigated mechanisms dampening the response to the FLT3 inhibitor quizartinib, which is specific to the hematopoietic niche. Using AML primary samples and cell lines, we demonstrate that convergent signals from the hematopoietic microenvironment drive FLT3-ITD cell resistance to quizartinib through the expression and activation of the tyrosine kinase receptor AXL. Indeed, cytokines sustained phosphorylation of the transcription factor STAT5 in quizartinib-treated cells, which enhanced AXL expression by direct binding of a conserved motif in its genomic sequence. Likewise, hypoxia, another well-known hematopoietic niche hallmark, also enhanced AXL expression. Finally, in a xenograft mouse model, inhibition of AXL significantly increased the response of FLT3-ITD cells to quizartinib exclusively within a bone marrow environment. These data highlight a new bypass mechanism specific to the hematopoietic niche that hampers the response to quizartinib through combined upregulation of AXL activity. Targeting this signaling offers the prospect of a new therapy to eradicate resistant FLT3-ITD leukemic cells hidden within their specific microenvironment, thereby preventing relapses from FLT3-ITD clones.
Asunto(s)
Benzotiazoles/farmacología , Resistencia a Antineoplásicos , Leucemia Mieloide Aguda/metabolismo , Compuestos de Fenilurea/farmacología , Proteínas Proto-Oncogénicas/biosíntesis , Proteínas Tirosina Quinasas Receptoras/biosíntesis , Factor de Transcripción STAT5/metabolismo , Microambiente Tumoral , Tirosina Quinasa 3 Similar a fms/metabolismo , Hipoxia de la Célula , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Humanos , Células K562 , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Proteínas Proto-Oncogénicas/genética , Proteínas Tirosina Quinasas Receptoras/genética , Factor de Transcripción STAT5/genética , Regulación hacia Arriba/efectos de los fármacos , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa del Receptor AxlAsunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Factor de Transcripción STAT5/fisiología , Antineoplásicos , Benzamidas/uso terapéutico , Supervivencia Celular , Resistencia a Antineoplásicos , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Proteínas de Fusión bcr-abl/fisiología , Genes abl/genética , Células Madre Hematopoyéticas/fisiología , Humanos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Recurrencia Local de Neoplasia/prevención & control , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/uso terapéuticoRESUMEN
The role of oxygen tension level is a well-known phenomenon that has been studied in oncology and radiotherapy since about 60 years. Oxygen tension may inhibit or stimulate propagation of viruses in vitro as well as in vivo. In turn modulating oxygen metabolism may constitute a novel approach to treat viral infections as an adjuvant therapy. The major transcription factor which regulates oxygen tension level is hypoxia-inducible factor-1 alpha (HIF-1α). Down-regulating the expression of HIF-1α is a possible method in the treatment of chronic viral infection such as human immunodeficiency virus infection, chronic hepatitis B and C viral infections and Kaposi sarcoma in addition to classic chemotherapy. The aim of this review is to supply an updating concerning the influence of oxygen tension level in human viral infections and to evoke possible new therapeutic strategies regarding this environmental condition.
Asunto(s)
Antivirales/metabolismo , Quimioterapia/métodos , Oxígeno/metabolismo , Virosis/tratamiento farmacológico , Quimioterapia Combinada/métodos , HumanosRESUMEN
STAT5 fulfills essential roles in hematopoietic stem cell (HSC) self-renewal and chronic myeloid leukemia (CML), a prototypical stem cell malignancy. However, the specific contributions of the two related genes STAT5A and STAT5B have not been determined. In this study, we used a RNAi-based strategy to establish participation of these genes to CML disease and persistence following targeted therapy. We showed that STAT5A/STAT5B double-knockdown triggers CML cell apoptosis and suppresses both normal and CML HSC long-term clonogenic potential. STAT5A and STAT5B exhibited similar prosurvival activity, but STAT5A attenuation alone was ineffective at impairing growth of normal and CML CD34(+) cells isolated at diagnosis. In contrast, STAT5A attenuation was sufficient to enhance basal oxidative stress and DNA damage of normal CD34(+) and CML cells. Furthermore, it weakened the ability to manage exogenous oxidative stress, increased p53 (TRP53)/CHK-2 (CHEK2) stress pathway activation, and enhanced prolyl hydroxylase domain (PHD)-3 (EGLN3) mRNA expression. Only STAT5A and its transactivation domain-deficient mutant STAT5AΔ749 specifically rescued these activities. STAT5A attenuation was also active at inhibiting growth of CML CD34(+) cells from patients with acquired resistance to imatinib. Our findings show that STAT5A has a selective role in contributing to stress resistance through unconventional mechanisms, offering new opportunities to eradicate the most primitive and tyrosine kinase inhibitor-resistant CML cells with an additional potential to eradicate persistent stem cell populations.