Hypoxia and Hypoxia-Inducible Factors in Leukemias.
Hypoxia and Hypoxia-Inducible Factors in Leukemias.
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DOI：
10.3389/fonc.2016.00041
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发表时间：
2016
影响因子：
4.7
通讯作者：
Mazurier F
中科院分区：
文献类型：
--
作者：
Deynoux M;Sunter N;Hérault O;Mazurier F
尽管白血病的治疗有了巨大的进步，但复发患者的比例仍然很高。复发最常见的原因是骨髓中的少量白血病干细胞（LSC），它们能够自我更新，因此重建整个肿瘤。骨髓微环境在支持白血病细胞的保护和发育方面有相当大的贡献。LSC与正常造血干细胞共享特定的小生境，小生境本身由多种细胞类型组成，包括间充质干细胞/基质细胞、骨细胞、免疫细胞、神经元细胞和血管细胞。造血生态位的标志是低氧分压，实际上这种缺氧对于造血干细胞/祖细胞的长期维持是必要的。缺氧是一种强信号，主要由缺氧诱导因子（HIF）家族成员维持。在实体瘤中，已经充分确定缺氧通过激活HIF触发内在代谢变化和微环境改变，例如刺激血管生成。由于白血病不被认为是一种“实体”肿瘤，氧在疾病中的作用被认为是无关紧要的，长期以来一直被忽视。这一观点现在已经被修正，因为缺氧已被证明会影响白血病细胞的增殖，分化和对化疗的耐药性。然而，HIF蛋白的作用仍然存在争议，HIF被认为是癌基因或肿瘤抑制基因，这取决于研究和模型。这篇综述的目的是强调我们的知识缺氧和HIF在白血病的发展和治疗耐药性，并讨论最近提出的缺氧为基础的战略，以消除白血病。
Despite huge improvements in the treatment of leukemia, the percentage of patients suffering relapse still remains significant. Relapse most often results from a small number of leukemic stem cells (LSCs) within the bone marrow, which are able to self-renew, and therefore reestablish the full tumor. The marrow microenvironment contributes considerably in supporting the protection and development of leukemic cells. LSCs share specific niches with normal hematopoietic stem cells with the niche itself being composed of a variety of cell types, including mesenchymal stem/stromal cells, bone cells, immune cells, neuronal cells, and vascular cells. A hallmark of the hematopoietic niche is low oxygen partial pressure, indeed this hypoxia is necessary for the long-term maintenance of hematopoietic stem/progenitor cells. Hypoxia is a strong signal, principally maintained by members of the hypoxia-inducible factor (HIF) family. In solid tumors, it has been well established that hypoxia triggers intrinsic metabolic changes and microenvironmental modifications, such as the stimulation of angiogenesis, through activation of HIFs. As leukemia is not considered a “solid” tumor, the role of oxygen in the disease was presumed to be inconsequential and remained long overlooked. This view has now been revised since hypoxia has been shown to influence leukemic cell proliferation, differentiation, and resistance to chemotherapy. However, the role of HIF proteins remains controversial with HIFs being considered as either oncogenes or tumor suppressor genes, depending on the study and model. The purpose of this review is to highlight our knowledge of hypoxia and HIFs in leukemic development and therapeutic resistance and to discuss the recent hypoxia-based strategies proposed to eradicate leukemias.