RESUMO

We have identified a precursor that differentiates into granulocytes in vitro and in vivo yet belongs to the monocytic lineage. We have termed these cells monocyte-like precursors of granulocytes (MLPGs). Under steady state conditions, MLPGs were absent in the spleen and barely detectable in the bone marrow (BM). In contrast, these cells significantly expanded in tumor-bearing mice and differentiated to polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Selective depletion of monocytic cells had no effect on the number of granulocytes in naive mice but decreased the population of PMN-MDSCs in tumor-bearing mice by 50%. The expansion of MLPGs was found to be controlled by the down-regulation of Rb1, but not IRF8, which is known to regulate the expansion of PMN-MDSCs from classic granulocyte precursors. In cancer patients, putative MLPGs were found within the population of CXCR1+CD15-CD14+HLA-DR-/lo monocytic cells. These findings describe a mechanism of abnormal myelopoiesis in cancer and suggest potential new approaches for selective targeting of MDSCs.

Assuntos

Monócitos/patologia , Células Supressoras Mieloides/patologia , Neoplasias/patologia , Neutrófilos/patologia , Adulto , Idoso , Animais , Diferenciação Celular , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Proteínas de Ligação a Retinoblastoma/metabolismo

RESUMO

Prolonged exit from quiescence by hematopoietic stem cells (HSCs) progressively impairs their homeostasis in the bone marrow through an unidentified mechanism. We show that Rb proteins, which are major enforcers of quiescence, maintain HSC homeostasis by positively regulating thrombopoietin (Tpo)-mediated Jak2 signaling. Rb family protein inactivation triggers the progressive E2f-mediated transactivation of Socs3, a potent inhibitor of Jak2 signaling, in cycling HSCs. Aberrant activation of Socs3 impairs Tpo signaling and leads to impaired HSC homeostasis. Therefore, Rb proteins act as a central hub of quiescence and homeostasis by coordinating the regulation of both cell cycle and Jak2 signaling in HSCs.

Assuntos

Células-Tronco Hematopoéticas/metabolismo , Homeostase/genética , Proteína do Retinoblastoma/genética , Proteína p107 Retinoblastoma-Like/genética , Proteína p130 Retinoblastoma-Like/genética , Proteína 3 Supressora da Sinalização de Citocinas/genética , Animais , Ciclo Celular/genética , Divisão Celular/genética , Proliferação de Células/genética , Fatores de Transcrição E2F/genética , Fatores de Transcrição E2F/metabolismo , Perfilação da Expressão Gênica/métodos , Immunoblotting , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Camundongos Knockout , Camundongos Transgênicos , Fosforilação/efeitos dos fármacos , Interferência de RNA , Proteína do Retinoblastoma/metabolismo , Proteína p107 Retinoblastoma-Like/metabolismo , Proteína p130 Retinoblastoma-Like/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Trombopoetina/farmacologia , Ativação Transcricional