Assuntos
Sistemas CRISPR-Cas/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Leucemia/genética , Osteonectina/genética , Animais , Progressão da Doença , Edição de Genes/métodos , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Xenoenxertos , Humanos , Leucemia/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Microambiente Tumoral/genéticaRESUMO
Myelodysplastic syndromes (MDSs) represent clonal disorders mainly of the elderly that are characterized by ineffective hematopoiesis and an increased risk of transformation into acute myeloid leukemia. The pathogenesis of MDS is thought to evolve from accumulation and selection of specific genetic or epigenetic events. Emerging evidence indicates that MDS is not solely a hematopoietic disease but rather affects the entire bone marrow microenvironment, including bone metabolism. Many of these cells, in particular mesenchymal stem and progenitor cells (MSPCs) and osteoblasts, express a number of adhesion molecules and secreted factors that regulate blood regeneration throughout life by contributing to hematopoietic stem and progenitor cell (HSPC) maintenance, self-renewal and differentiation. Several endocrine factors, such as erythropoietin, parathyroid hormone and estrogens, as well as deranged iron metabolism modulate these processes. Thus, interactions between MSPC and HSPC contribute to the pathogenesis of MDS and associated pathologies. A detailed understanding of these mechanisms may help to define novel targets for diagnosis and possibly therapy. In this review, we will discuss the scientific rationale of 'osteohematology' as an emerging research field in MDS and outline clinical implications.
Assuntos
Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/patologia , Animais , Medula Óssea/patologia , Citocinas/metabolismo , Progressão da Doença , Epigênese Genética , Eritropoetina/metabolismo , Células-Tronco Hematopoéticas/citologia , Humanos , Ferro/química , Sobrecarga de Ferro/metabolismo , Células-Tronco Mesenquimais/citologia , Osteoblastos/citologia , Hormônio Paratireóideo/metabolismo , Transdução de SinaisAssuntos
Técnicas de Transferência de Genes , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Animais , Proliferação de Células , Humanos , Interleucina-7/farmacologia , Lentivirus/genética , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Transdução Genética , Proteínas do Envelope Viral/genéticaRESUMO
Signal transducers and activator of transcription 5 (STAT5) A and B are transcriptional regulators that play a central role in cytokine signaling in the hematopoietic lineage and which are frequently activated in a persistent manner in human leukemia/lymphoma, as assessed by their constitutive tyrosine phosphorylation and DNA-binding activity. To study the intrinsic oncogenic properties of persistent STAT5 activation, we generated transgenic mice in which a constitutively activated point mutant of STAT5A, STAT5A(S711F), was expressed at physiological level in their lymphoid compartment. In this model, persistent STAT5 activation is weakly oncogenic, leading to the late emergence of clonal B-cell lymphoma/leukemia at a low incidence. In contrast, STAT5(S711F) was found to cooperate with the loss of function of the p53 tumor suppressor gene to both accelerate disease onset and to skew the large tumor spectrum that normally characterize p53-deficient mice to strongly favor B-cell lymphoma/leukemia. The emergence of STAT5A(S711F)-induced B-cell tumors is associated with the activation of STAT5 tyrosine phosphorylation and DNA-binding activity, indicating that activation of STAT5 oncogenic properties in transgenic STAT5A (TgSTAT5A) (S711F) mice involves the deregulation of STAT5 phosphorylation dynamics.