Department of Medical Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands; Division of Neurobiology, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
Department of Medical Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
Biochim Biophys Acta Rev Cancer. 2017 Aug;1868(1):183-198. doi: 10.1016/j.bbcan.2017.03.010. Epub 2017 Mar 28.
Acute myeloid leukemia and acute lymphoblastic leukemia cells hijack hematopoietic stem cell (HSC) niches in the bone marrow and become leukemic stem cells (LSCs) at the expense of normal HSCs. LSCs are quiescent and resistant to chemotherapy and can cause relapse of the disease. HSCs in niches are needed to generate blood cell precursors that are committed to unilineage differentiation and eventually production of mature blood cells, including red blood cells, megakaryocytes, myeloid cells and lymphocytes. Thus far, three types of HSC niches are recognized: endosteal, reticular and perivascular niches. However, we argue here that there is only one type of HSC niche, which consists of a periarteriolar compartment and a perisinusoidal compartment. In the periarteriolar compartment, hypoxia and low levels of reactive oxygen species preserve the HSC pool. In the perisinusoidal compartment, hypoxia in combination with higher levels of reactive oxygen species enables proliferation of progenitor cells and their mobilization into the circulation. Because HSC niches offer protection to LSCs against chemotherapy, we review novel therapeutic strategies to inhibit homing of LSCs in niches for the prevention of dedifferentiation of leukemic cells into LSCs and to stimulate migration of leukemic cells out of niches. These strategies enhance differentiation and proliferation and thus sensitize leukemic cells to chemotherapy. Finally, we list clinical trials of therapies that tackle LSCs in HSC niches to circumvent their protection against chemotherapy.
急性髓细胞白血病和急性淋巴细胞白血病细胞劫持骨髓中的造血干细胞（HSC）龛位，并以正常 HSC 为代价成为白血病干细胞（LSC）。LSC 处于静止状态且对化疗有抵抗力，并可能导致疾病复发。龛位中的 HSC 用于生成向单系分化并最终产生成熟血细胞（包括红细胞、巨核细胞、髓细胞和淋巴细胞）的血细胞前体。迄今为止，已经识别出三种类型的 HSC 龛位：骨内膜、网状和血管周龛位。然而，我们在这里认为，只有一种 HSC 龛位，它由一个动-静脉周围间隙和一个窦周间隙组成。在动-静脉周围间隙中，缺氧和低水平的活性氧维持 HSC 池。在窦周间隙中，缺氧与较高水平的活性氧结合使祖细胞增殖并动员到循环中。由于 HSC 龛位为 LSC 提供了对化疗的保护，我们综述了抑制 LSC 归巢到龛位的新治疗策略，以防止白血病细胞向 LSC 去分化，并刺激白血病细胞从龛位中迁移。这些策略增强了分化和增殖，从而使白血病细胞对化疗敏感。最后，我们列出了针对 HSC 龛位中 LSC 的治疗方法的临床试验，以规避它们对化疗的保护作用。
