DeKoter R P, Walsh J C, Singh H
Department of Molecular Genetics and Cell Biology, The University of Chicago, IL 60637, USA.
EMBO J. 1998 Aug 3;17(15):4456-68. doi: 10.1093/emboj/17.15.4456.
PU.1 is a unique regulatory protein required for the generation of both the innate and the adaptive immune system. It functions exclusively in a cell-intrinsic manner to control the development of granulocytes, macrophages, and B and T lymphocytes. We demonstrate that mutation of the PU.1 gene causes a severe reduction in myeloid (granulocyte/macrophage) progenitors. PU.1 -/- myeloid progenitors can proliferate in vitro in response to the multilineage cytokines interleukin-3 (IL-3), IL-6 and stem cell factor but are unresponsive to the myeloid-specific cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF and M-CSF. The failure of PU.1 -/- progenitors to respond to G-CSF is bypassed by transient signaling with IL-3. In the presence of IL-3 and G-CSF, PU.1 -/- progenitors can differentiate into granulocytic precursors containing myeloperoxidase-positive granules. Thus PU.1 is not essential for specification of granulocytic precursors, but is required for their further differentiation. The failure of PU.1 -/- progenitors to respond to M-CSF is due to lack of c-fms gene transcription. Transduction of c-fms into PU.1 -/- myeloid progenitors bypasses the block to M-CSF-dependent proliferation but does not induce detectable macrophage differentiation. Therefore, PU. 1 appears to be essential for specification of monocytic precursors. Importantly, retroviral transduction of PU.1 into mutant progenitors restores responsiveness to myeloid-specific cytokines and development of mature granulocytes and macrophages. Thus PU.1 controls myelopoiesis by regulating both proliferation and differentiation pathways.
PU.1是一种独特的调节蛋白，对于先天性和适应性免疫系统的生成均必不可少。它仅以细胞内源性方式发挥作用，以控制粒细胞、巨噬细胞以及B和T淋巴细胞的发育。我们证明，PU.1基因的突变会导致髓系（粒细胞/巨噬细胞）祖细胞严重减少。PU.1基因敲除的髓系祖细胞可在体外对多谱系细胞因子白细胞介素-3（IL-3）、IL-6和干细胞因子作出反应而增殖，但对髓系特异性细胞因子粒细胞-巨噬细胞集落刺激因子（GM-CSF）、粒细胞集落刺激因子（G-CSF）和巨噬细胞集落刺激因子（M-CSF）无反应。IL-3的短暂信号传导可绕过PU.1基因敲除的祖细胞对G-CSF无反应的情况。在存在IL-3和G-CSF的情况下，PU.1基因敲除的祖细胞可分化为含有髓过氧化物酶阳性颗粒的粒细胞前体。因此，PU.1对于粒细胞前体的特化并非必不可少，但对于其进一步分化却是必需的。PU.1基因敲除的祖细胞对M-CSF无反应是由于缺乏c-fms基因转录。将c-fms转导至PU.1基因敲除的髓系祖细胞中可绕过对M-CSF依赖性增殖的阻滞，但不会诱导可检测到的巨噬细胞分化。因此，PU.1似乎对于单核细胞前体的特化至关重要。重要的是，将PU.1逆转录病毒转导至突变祖细胞中可恢复对髓系特异性细胞因子的反应性以及成熟粒细胞和巨噬细胞的发育。因此，PU.1通过调节增殖和分化途径来控制髓系造血。
