Wolff Linda, Garin Matthew T, Koller Richard, Bies Juraj, Liao Wei, Malumbres Marcos, Tessarollo Lino, Powell Douglas, Perella Christine
Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892-4255, USA.
Oncogene. 2003 Dec 18;22(58):9265-74. doi: 10.1038/sj.onc.1207092.
The Ink4b gene (Cdkn2b) encodes p15(Ink4b), a cyclin-dependent kinase inhibitor. It has been implicated in playing a role in the development of acute myeloid leukemia (AML) in man, since it is hypermethylated with high frequency. We provide evidence that the gene is a tumor suppressor for myeloid leukemia in mice. The evidence is twofold: (1) retrovirus-induced myeloid leukemias of the myelomonocytic phenotype were found to have hypermethylation of the 5' CpG island of the Ink4b gene, and this could be correlated with reduced mRNA expression, as demonstrated by TaqMan real-time PCR. p15(Ink4b) mRNA expression in a leukemia cell line, with hypermethylation at the locus, was induced following treatment with 5-aza-2'-deoxycytidine. (2) Targeted deletion of one allele in mice by removal of exon 2 increases their susceptibility to retrovirus-induced myeloid leukemia. Mice deficient in both alleles were not more susceptible to myeloid disease than those deficient in one allele, raising the possibility that there are opposing forces related to the development of myeloid leukemia in Ink4b null mice.
Ink4b基因（Cdkn2b）编码p15（Ink4b），一种细胞周期蛋白依赖性激酶抑制剂。由于其高频甲基化，它被认为在人类急性髓系白血病（AML）的发生中起作用。我们提供证据表明该基因是小鼠髓系白血病的肿瘤抑制基因。证据有两方面：（1）发现逆转录病毒诱导的髓单核细胞表型的髓系白血病中，Ink4b基因的5' CpG岛发生甲基化，这与mRNA表达降低相关，TaqMan实时PCR证明了这一点。用5-氮杂-2'-脱氧胞苷处理后，一个位点发生甲基化的白血病细胞系中p15（Ink4b）mRNA表达被诱导。（2）通过去除外显子2在小鼠中靶向缺失一个等位基因会增加它们对逆转录病毒诱导的髓系白血病的易感性。两个等位基因均缺失的小鼠并不比一个等位基因缺失的小鼠对髓系疾病更易感，这增加了在Ink4b基因敲除小鼠中存在与髓系白血病发生相关的相反作用力的可能性。
