Ellisen L W, Carlesso N, Cheng T, Scadden D T, Haber D A
Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.
EMBO J. 2001 Apr 17;20(8):1897-909. doi: 10.1093/emboj/20.8.1897.
WT1, a transcription factor implicated in both normal kidney differentiation and tumorigenesis, is also expressed in differentiating hematopoietic progenitors. Most human acute leukemias contain high levels of the wild-type transcript, while a minority have point mutations, raising the possibility that this tumor suppressor might have a paradoxical oncogenic effect in some hematopoietic cells. Using high titer retroviral infection, we demonstrate that WT1 triggers rapid growth arrest and lineage-specific differentiation in primary hematopoietic progenitors and differentiation-competent leukemia cell lines, while it induces cellular quiescence in a primitive subset of primary precursors. Growth arrest by WT1 is associated with induction of p21(CIP1), but expression of this cyclin-dependent kinase inhibitor alone is insufficient for either cellular differentiation or primitive cell preservation. The effects of WT1 are enhanced by co-expression of its naturally occurring isoforms, and are correlated with the physiological expression pattern of WT1 in vivo. Our observations suggest a role for WT1 in the differentiation of human hematopoietic cells, and provide a functional model that supports its capacity as a tumor suppressor in human acute leukemia.
WT1是一种与正常肾脏分化和肿瘤发生均有关的转录因子，在分化中的造血祖细胞中也有表达。大多数人类急性白血病含有高水平的野生型转录本，而少数存在点突变，这增加了这种肿瘤抑制因子在某些造血细胞中可能具有矛盾致癌作用的可能性。通过高滴度逆转录病毒感染，我们证明WT1在原代造血祖细胞和具有分化能力的白血病细胞系中触发快速生长停滞和谱系特异性分化，而在原代前体细胞的一个原始亚群中诱导细胞静止。WT1引起的生长停滞与p21（CIP1）的诱导有关，但仅这种细胞周期蛋白依赖性激酶抑制剂的表达不足以实现细胞分化或原始细胞保存。WT1的天然异构体共表达可增强其作用，并与WT1在体内的生理表达模式相关。我们的观察结果表明WT1在人类造血细胞分化中发挥作用，并提供了一个功能模型，支持其作为人类急性白血病肿瘤抑制因子的能力。
