Haidar M A, Cao X B, Manshouri T, Chan L L, Glassman A, Kantarjian H M, Keating M J, Beran M S, Albitar M
Division of Laboratory Medicine and Medicine, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Blood. 1995 Jul 1;86(1):311-5.
The 9p21 locus has been deleted at a high frequency in a wide variety of tumors. Recently, two genes, p16INK4A and p15INK4B (also called MTS1 and MTS2), have been localized in close proximity at the 9p21 locus, encoding cyclin-dependent kinases 4/6 inhibitors of relative molecular mass 16 kD and 15 kD, respectively and also found to be deleted at a high frequency in tumor cell lines. We analyzed p16INK4A and p15INK4B genes in 178 cases of primary leukemias including 81 cases of chronic lymphocytic leukemia (CLL), seven of hairy cell leukemia (HCL), seven of chronic myelogenous leukemia (CML), 43 of acute myelogenous leukemia (AML), 27 of acute lymphoblastic leukemia (ALL), and 13 of myelodysplastic syndrome (MDS) by Southern blot analyses. The ALL cases showed a relatively high frequency of homozygous deletions (22%, 6 of 27) at the p16INK4A gene locus. Interestingly, of the six cases with p16INK4A homozygous deletions, only three showed homozygous deletions at the p15INK4B gene. In 81 CLL patients, we detected one homozygous and five heterozygous deletions at both the p16INK4A and p15INK4B genes and two heterozygous deletions at the p16INK4A gene alone. Deletion of these two genes in AML cases is relatively low (9%). We did not detect deletions in any of the MDS, HCL, and CML cases examined. Sequence analyses of p16INK4A gene of six CLL cases with heterozygous deletion at this locus showed a 27-bp deletion at the splice acceptor site of intron 1 in one case and changes in the coding sequence in three other cases. The data presented in this report showed that (1) p16INK4A and p15INK4B genes are preferentially deleted homozygously in ALL and heterozygously in CLL cases with frequent mutation in the second allele, and (2) p16INK4A gene appears to be more frequently deleted than p15INK4B gene.
9p21位点在多种肿瘤中高频缺失。最近，两个基因p16INK4A和p15INK4B（也称为MTS1和MTS2）定位于9p21位点附近，分别编码相对分子质量为16kD和15kD的细胞周期蛋白依赖性激酶4/6抑制剂，并且在肿瘤细胞系中也高频缺失。我们通过Southern印迹分析检测了178例原发性白血病中的p16INK4A和p15INK4B基因，其中包括81例慢性淋巴细胞白血病（CLL）、7例毛细胞白血病（HCL）、7例慢性粒细胞白血病（CML）、43例急性髓细胞白血病（AML）、27例急性淋巴细胞白血病（ALL）和13例骨髓增生异常综合征（MDS）。ALL病例在p16INK4A基因位点显示出相对较高频率的纯合缺失（22%，27例中的6例）。有趣的是，在6例p16INK4A纯合缺失的病例中，只有3例在p15INK4B基因显示纯合缺失。在81例CLL患者中，我们在p16INK4A和p15INK4B基因检测到1例纯合缺失和5例杂合缺失，在p16INK4A基因单独检测到2例杂合缺失。AML病例中这两个基因的缺失相对较低（9%）。在检测的任何MDS、HCL和CML病例中我们均未检测到缺失。对6例在此位点杂合缺失的CLL病例的p16INK4A基因进行序列分析，发现1例在第1内含子的剪接受体位点有27bp缺失，另外3例在编码序列有改变。本报告中的数据表明：（1）p16INK4A和p15INK4B基因在ALL中优先发生纯合缺失，在CLL中发生杂合缺失且第二个等位基因频繁突变；（2）p16INK4A基因似乎比p15INK4B基因更频繁地发生缺失。
