RESUMO
Enteropathy-associated T-cell lymphoma (EATL) is a rare aggressive lymphoma that confers a poor prognosis with current treatment strategies. Given the rarity of this disease, prospective randomized trials are limited, and thus a standard validated treatment strategy is lacking. This report presents the disease course of a patient with EATL who was treated with single-agent brentuximab vedotin, an anti-CD30 conjugated antibody.
Assuntos
Linfoma de Células T Associado a Enteropatia/tratamento farmacológico , Linfoma de Células T Associado a Enteropatia/imunologia , Imunoconjugados/uso terapêutico , Antígeno Ki-1/imunologia , Anticorpos/imunologia , Brentuximab Vedotin , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
p21(ras) (Ras) proteins and GTPase-activating proteins (GAPs) tightly modulate extracellular growth factor signals and control multiple cellular functions. The specific function of each Ras isoform (H, N, and K) in regulating distinct effector pathways, and the role of each GAP in negatively modulating the activity of each Ras isoform in myeloid cells and, particularly, mast cells is incompletely understood. In this study, we use murine models of K-ras- and Nf1-deficient mice to examine the role of K-ras in modulating mast cell functions and to identify the role of neurofibromin as a GAP for K-ras in this lineage. We find that K-ras is required for c-kit-mediated mast cell proliferation, survival, migration, and degranulation in vitro and in vivo. Furthermore, the hyperactivation of these cellular functions in Nf1(+/-) mast cells is decreased in a K-ras gene dose-dependent fashion in cells containing mutations in both loci. These findings identify K-ras as a key effector in multiple mast cell functions and identify neurofibromin as a GAP for K-ras in mast cells.
Assuntos
Degranulação Celular/imunologia , Movimento Celular/imunologia , Proliferação de Células , Mastócitos/imunologia , Neurofibromina 1/imunologia , Proteínas Proto-Oncogênicas c-kit/imunologia , Proteínas Proto-Oncogênicas p21(ras)/imunologia , Animais , Degranulação Celular/genética , Movimento Celular/genética , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Células Cultivadas , Camundongos , Camundongos Knockout , Mutação , Neurofibromina 1/deficiência , Proteínas Proto-Oncogênicas p21(ras)/deficiência , Locos de Características Quantitativas/genética , Locos de Características Quantitativas/imunologiaRESUMO
In vitro studies suggest that Ras activation is necessary for erythroid cell development. However, genetic inactivation of the Ras isoforms H-Ras, N-Ras, and K-Ras in mice reportedly did not affect adult or fetal erythropoiesis, though K-Ras(-/-) embryos were anemic. Given these discrepancies, we performed a more detailed analysis of fetal erythropoiesis in K-Ras(-/-) embryos. Day-13.5 K-Ras(-/-) embryos were pale with a marked reduction of mature erythrocytes in their fetal livers. The frequency and number of both early (erythroid burst-forming unit [BFU-E]) and late erythroid progenitors (erythroid colony-forming unit [CFU-E]) were reduced in K-Ras(-/-) fetal livers compared with wild-type controls and displayed a delay in terminal erythroid cell maturation. Further, K-Ras(-/-) hematopoietic progenitors had reduced proliferation in response to erythropoietin and Kit ligand compared with control cells. Thus, these studies identify K-Ras as a unique Ras isoform that is essential for regulating fetal erythropoiesis in vivo.