Onodera N, McCabe N R, Rubin C M
Department of Pediatrics, University of Chicago, IL 60637.
Blood. 1992 Jul 1;80(1):203-8.
Hyperdiploidy with greater than or equal to 50 chromosomes is a frequent and distinct karyotypic pattern in the malignant cells of children with acute lymphoblastic leukemia. To understand better the mechanism of formation of the hyperdiploid karyotype, we studied 15 patients using 20 DNA probes that detect restriction fragment length polymorphisms. We first examined disomic chromosomes for loss of heterozygosity. Two patients had widespread loss of heterozygosity on all informative disomic chromosomes, and represent cases of near-haploid leukemia in which the chromosomes doubled. One other patient had loss of heterozygosity limited to chromosome 3; in this patient all of seven other informative disomic chromosomes retained heterozygosity. Loss of heterozygosity was not detected in the remaining 12 patients on a total of 87 informative disomic chromosomes. We then examined tetrasomic chromosomes for parental dosage. Of the 13 patients in whom widespread loss of heterozygosity was not present, 11 patients had tetrasomy 21; 10 of 11 (91%) had an equal dose of maternal and paternal alleles on chromosome 21 and only 1 of 11 (9%) had an unequal dose of parental alleles in a 3:1 ratio. These results suggest that the hyperdiploid karyotype usually arises by simultaneous gain of chromosomes from a diploid karyotype during a single abnormal cell division, and occasionally by doubling of chromosomes from a near-haploid karyotype. The hyperdiploidy in cases without widespread loss of heterozygosity is not caused by stepwise or sequential gains from a diploid karyotype or by losses from a tetraploid karyotype; the former should result in a 3:1 parental dosage for 67% of tetrasomic chromosomes (9% observed) and the latter should result in loss of heterozygosity for 33% of disomic chromosomes (1% observed). Additional studies of the molecular basis for this leukemia subtype are warranted.
染色体数目大于或等于50条的超二倍体是急性淋巴细胞白血病患儿恶性细胞中常见且独特的核型模式。为了更好地理解超二倍体核型的形成机制，我们使用20种检测限制性片段长度多态性的DNA探针研究了15例患者。我们首先检查二体染色体的杂合性缺失情况。两名患者在所有有信息的二体染色体上均出现广泛的杂合性缺失，代表了近单倍体白血病病例，其中染色体发生了加倍。另一名患者的杂合性缺失仅限于3号染色体；在该患者中，其他7条有信息的二体染色体均保留了杂合性。在其余12例患者的总共87条有信息的二体染色体上未检测到杂合性缺失。然后我们检查了四体染色体的亲本剂量。在13例未出现广泛杂合性缺失的患者中，11例患者存在21号染色体四体；11例中的10例（91%）在21号染色体上母本和父本等位基因剂量相等，只有11例中的1例（9%）亲本等位基因剂量呈3:1不等比例。这些结果表明，超二倍体核型通常是在一次异常细胞分裂过程中从二倍体核型同时获得染色体而产生的，偶尔也会由近单倍体核型的染色体加倍产生。在没有广泛杂合性缺失的病例中，超二倍体并非由二倍体核型的逐步或顺序获得或四倍体核型的缺失引起；前者应导致67%的四体染色体出现3:1的亲本剂量（观察到9%），后者应导致33%的二体染色体出现杂合性缺失（观察到1%）。有必要对这种白血病亚型的分子基础进行进一步研究。
