Iravani M, Dhat R, Price C M
Leukaemia Research Fund Centre, Institute of Cancer Research, Chester Beatty Laboratories, London, UK.
Oncogene. 1997 Nov 20;15(21):2609-14. doi: 10.1038/sj.onc.1201428.
The multi tumor suppressor genes MTS1 (CDKN2 p16INK4A) and MTS2 (CDKN1, p15INK4B) located at 9p21-22 are inactivated in some human cancers via several mechanisms including deletion and hypermethylation. We have investigated the deletion and methylation status of MTS1 and MTS2 in childhood acute lymphoblastic leukemia (ALL) of both T-cell (17 cases) and B-cell phenotypes (29 cases), and p16INK4A and p15INK4B mRNA expression in 36 of these cases. Biallelic or monoallelic loss of both MTS1 and MTS2 was observed in 12 cases of B-ALL and nine cases of T-ALL. Two cases of T-ALL showed deletion of MTS1 but not MTS2. The 5' CpG region of MTS2 was hypermethylated in 12 cases of precursor B-ALL and eight cases of T-ALL but no hypermethylation was found in the 5' CpG region of MTS1. All cases with homozygous deletion of MTS1 or MTS2 had no or low levels of mRNA expression and similar low levels of expression were found in cases in which MTS2 was present but fully methylated. Thus hypermethylation of MTS2, in contrast to MTS1, is frequent in childhood ALL. Furthermore our data show that although inactivation of MTS1 by deletion is common, inactivation of MTS2 by a combination of deletion and hypermethylation is more frequent in both B-ALL (20/29, 69%) and T-ALL (17/17, 100%). This suggests that both MTS1 and MTS2 are important targets of the 9p21-22 deletion.
位于9p21 - 22的多肿瘤抑制基因MTS1（CDKN2 p16INK4A）和MTS2（CDKN1，p15INK4B）在一些人类癌症中通过包括缺失和高甲基化在内的多种机制失活。我们研究了T细胞型（17例）和B细胞型（29例）儿童急性淋巴细胞白血病（ALL）中MTS1和MTS2的缺失及甲基化状态，以及其中36例病例中p16INK4A和p15INK4B的mRNA表达。在12例B - ALL和9例T - ALL中观察到MTS1和MTS2的双等位基因或单等位基因缺失。2例T - ALL显示MTS1缺失但MTS2未缺失。MTS2的5' CpG区域在12例前体B - ALL和8例T - ALL中发生高甲基化，但在MTS1的5' CpG区域未发现高甲基化。所有MTS1或MTS2纯合缺失的病例均无或仅有低水平的mRNA表达，并且在MTS2存在但完全甲基化的病例中也发现了类似的低水平表达。因此，与MTS1相比，MTS2的高甲基化在儿童ALL中较为常见。此外，我们的数据表明，虽然通过缺失使MTS1失活很常见，但在B - ALL（20/29，69%）和T - ALL（17/17，100%）中，通过缺失和高甲基化相结合使MTS2失活更为频繁。这表明MTS1和MTS2都是9p21 - 22缺失的重要靶点。
