Kikushige Yoshikane, Yoshimoto Goichi, Miyamoto Toshihiro, Iino Tadafumi, Mori Yasuo, Iwasaki Hiromi, Niiro Hiroaki, Takenaka Katsuto, Nagafuji Koji, Harada Mine, Ishikawa Fumihiko, Akashi Koichi
Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
J Immunol. 2008 Jun 1;180(11):7358-67. doi: 10.4049/jimmunol.180.11.7358.
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.
FLT3/FLK2是受体酪氨酸激酶家族的成员之一，在维持造血稳态中起关键作用，FLT3突变的组成型激活形式是急性髓性白血病中最常见的基因异常之一。在小鼠造血过程中，Flt3在自我更新的造血干细胞中不表达，但其表达仅限于多能和淋巴祖细胞阶段，而这些细胞无法自我更新。我们广泛分析了Flt3在人类造血过程中的表达。令人惊讶的是，在骨髓和脐血中，能够在异种宿主中长期重建的人类造血干细胞群体均一致表达Flt3。此外，人类Flt3不仅在早期淋巴祖细胞中表达，而且在沿粒细胞/巨噬细胞途径的祖细胞中持续表达，包括常见髓系祖细胞和粒细胞/巨噬细胞祖细胞。我们进一步发现，人类Flt3信号至少通过上调Mcl-1（造血过程中不可或缺的生存因子）来防止干细胞和祖细胞发生自发性凋亡细胞死亡。因此，Flt3表达的分布在人类和小鼠造血过程中有很大差异，人类FLT3信号可能在细胞存活中起重要作用，尤其是在急性髓性白血病转化的关键细胞靶点——干细胞和祖细胞中。
