Hirai Hideyo, Yokota Asumi, Tamura Akihiro, Sato Atsushi, Maekawa Taira
Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan.
Cancer Sci. 2015 Jul;106(7):797-802. doi: 10.1111/cas.12690. Epub 2015 Jun 1.
Steady-state hematopoiesis responds to extracellular stimuli to meet changing demands and also to pathologically altered intracellular signaling. Granulocyte production increases following infection or in response to cytokine stimulation, and activation of the CCAAT/enhancer-binding protein β (C/EBPβ) transcription factor is required for such stress-induced granulopoiesis, whereas C/EBPα plays a critical role in maintaining steady-state granulopoiesis. Different roles of these C/EBP transcription factors in different modes of hematopoiesis are evolutionally conserved from zebrafish to humans. In addition to reactions against infections, C/EBPβ is responsible for cancer-driven myelopoiesis, which promotes cancer progression, at least in part, by abrogating the immune response in the cancer microenvironment. The BCR-ABL fusion protein activates emergency-specific pathway of granulopoiesis by upregulating C/EBPβ. This in turn causes chronic phase chronic myeloid leukemia, which is characterized by myeloid expansion. The C/EBPβ transcription factor also plays a role in other hematological malignancies of both myeloid and lymphoid lineage origin. Thus, elucidation of the upstream and downstream networks surrounding C/EBPβ will lead to the development of novel therapeutic strategies for diseases mediated by non-steady-state hematopoiesis.
稳态造血对细胞外刺激作出反应，以满足不断变化的需求，同时也对细胞内信号的病理改变作出反应。感染后或对细胞因子刺激作出反应时，粒细胞生成会增加，而这种应激诱导的粒细胞生成需要CCAAT/增强子结合蛋白β（C/EBPβ）转录因子的激活，而C/EBPα在维持稳态粒细胞生成中起关键作用。从斑马鱼到人类，这些C/EBP转录因子在不同造血模式中的不同作用在进化上是保守的。除了对感染作出反应外，C/EBPβ还与癌症驱动的髓系造血有关，这至少部分通过消除癌症微环境中的免疫反应来促进癌症进展。BCR-ABL融合蛋白通过上调C/EBPβ激活粒细胞生成的应急特异性途径。这进而导致慢性期慢性髓性白血病，其特征是髓系扩增。C/EBPβ转录因子在起源于髓系和淋巴系的其他血液系统恶性肿瘤中也起作用。因此，阐明围绕C/EBPβ的上下游网络将导致开发针对由非稳态造血介导的疾病的新型治疗策略。
