期刊
EMBO JOURNAL
卷 20, 期 8, 页码 1897-1909出版社
WILEY
DOI: 10.1093/emboj/20.8.1897
关键词
hematopoiesis; leukemia; tumor suppressor; WT1
资金
- NCI NIH HHS [CA58596, CA82831, R01 CA058596, R37 CA058596] Funding Source: Medline
- NHLBI NIH HHS [R01 HL044851, HL44851] Funding Source: Medline
- NIDDK NIH HHS [DK02761, DK50234, R01 DK050234, K08 DK002761] Funding Source: Medline
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 I 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 coexpression 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.
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