期刊
BLOOD
卷 104, 期 12, 页码 3437-3444出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2004-06-2234
关键词
-
类别
资金
- NCI NIH HHS [CA80188] Funding Source: Medline
In most myeloid leukemias induced in mice by gamma-racliation, one copy of chromosome 2 has suffered a deletion. To search for a potential tumor suppressor gene in that region, we have delineated the deletions in a panel of these tumors. A commonly deleted region of 2 megabase pairs (Mbp) includes the gene encoding the PUA transcription factor, a powerful inducer of g ran u locytic/monocytic differentiation. Significantly, in 87% of these tumors the remaining PUA allele exhibited point mutations in the PUA DNA binding domain. Surprisingly, 86% of these mutations altered a single CpG, implicating deamination of deoxycytidine, a common mutational mechanism, as the origin of this lesion. The hot spot resides in the codon for a Contact residue essential for DNA binding by PU.1.. In keeping with a tumor suppressor role for PU.1, enforced expression of wild-type PU.1 in the promyelocytic leukemia cells inhibited their clonogenic growth, induced monocytic differentiation, and elicited apoptosis. The mutant PU.1. found in tumors retained only minimal growth suppressive function. The results suggest that PU.1 normally suppresses development of myeloid leukemia by promoting differentiation and that the combination of gene deletion and a point mutation that impairs its ability to bind DNA is particularly leukemogenic.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据