Human Flt3 is expressed at the hematopoietic stem cell and the granulocyte/macrophage progenitor stages to maintain cell survival
Human Flt3 is expressed at the hematopoietic stem cell and the granulocyte/macrophage progenitor stages to maintain cell survival
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DOI：
10.4049/jimmunol.180.11.7358
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发表时间：
2008-06-01
影响因子：
4.4
通讯作者：
Akashi, Koichi
中科院分区：
文献类型：
--
作者：
Kikushige, Yoshikane;Yoshimoto, Goichi;Akashi, Koichi
FLT3/FLK2是受体酪氨酸激酶家族的成员，在维持造血稳态中发挥着关键作用，FLT3突变的组成型活性形式是急性髓性白血病中最常见的遗传异常之一。在小鼠造血过程中，Flt3在自我更新的造血干细胞中不表达，但其表达仅限于细胞不能自我更新的多能和淋巴祖细胞阶段。我们广泛分析了 Flt3 在人类 (h) 造血过程中的表达。引人注目的是，在骨髓和脐带血中，能够在异种宿主中长期重建的人类造血干细胞群一致表达 Flt3。此外，人Flt3不仅在早期淋巴祖细胞中表达，而且在沿粒细胞/巨噬细胞途径的连续祖细胞中表达，包括常见的骨髓祖细胞和粒细胞/巨噬细胞祖细胞。我们进一步发现，人类 Flt3 信号传导至少通过上调 Mcl-1（造血不可或缺的生存因子）来防止干细胞和祖细胞自发性凋亡细胞死亡。因此，人类和小鼠造血过程中 Flt3 表达的分布有很大不同，人类 FLT3 信号传导可能在细胞存活中发挥重要作用，特别是在作为急性髓性白血病转化的关键细胞靶标的干细胞和祖细胞中。
FLT3/FLK2, a member of the receptor tyrosine kinase family, plays a critical role in maintenance of hematopoietic homeostasis, and the constitutively active form of the FLT3 mutation is one of the most common genetic abnormalities in acute myelogenous leukemia. In murine hematopoiesis, Flt3 is not expressed in self-renewing hematopoietic stem cells, but its expression is restricted to the multipotent and the lymphoid progenitor stages at which cells are incapable of self-renewal. We extensively analyzed the expression of Flt3 in human (h) hematopoiesis. Strikingly, in both the bone marrow and the cord blood, the human hematopoietic stem cell population capable of long-term reconstitution in xenogeneic hosts uniformly expressed Flt3. Furthermore, human Flt3 is expressed not only in early lymphoid progenitors, but also in progenitors continuously along the granulocyte/macrophage pathway, including the common myeloid progenitor and the granulocyte/macrophage progenitor. We further found that human Flt3 signaling prevents stem and progenitors from spontaneous apoptotic cell death at least through up-regulating Mcl-1, an indispensable survival factor for hematopoiesis. Thus, the distribution of Flt3 expression is considerably different in human and mouse hematopoiesis, and human FLT3 signaling might play an important role in cell survival, especially at stem and progenitor cells that are critical cellular targets for acute myelogenous leukemia transformation.