Sweetser David A, Peniket Andrew J, Haaland Christina, Blomberg Adam A, Zhang Yuntian, Zaidi Syed Tanweer, Dayyani Farshid, Zhao Zheng, Heerema Nyla A, Boultwood Jacqueline, Dewald Gordon W, Paietta Elisabeth, Slovak Marilyn L, Willman Cheryl L, Wainscoat James S, Bernstein Irwin D, Daly Sarah B
Department of Pediatrics, Massachusetts General Hospital, 55 Fruit Street--Jackson 904, Boston, MA 02114, USA.
Genes Chromosomes Cancer. 2005 Nov;44(3):279-91. doi: 10.1002/gcc.20236.
Deletion of the long arm of chromosome 9, del(9q), is a recurring chromosomal aberration in acute myeloid leukemia (AML) that is frequently associated with t(8;21). The critical gene products affected by del(9q) are unknown but likely cooperate with the AML1/ETO fusion gene created by t(8;21) in leukemogenesis. In 43 AML samples with del(9q), we used high-density microsatellite markers to define the commonly deleted region (CDR) to less than 2.4 Mb. We found no homozygous loss at any locus tested. The CDR contains 7 known genes, FRMD3, UBQLN1, GKAP42, KIF27, HNRPK, SLC28A3, and NTRK2, and 4 novel genes, RASEF, C9orf103, C9orf64, and C9orf76. In addition, TLE1 and TLE4 are adjacent to the CDR. We performed a comprehensive mutational analysis of the coding regions of all these genes. No sequence variations absent in normal controls were seen in more than a single del(9q) AML sample. Expression of 7 of the 10 genes examined was significantly down-regulated in del(19q)AML as compared with the CD34-purified progenitors from normal individuals, a pattern distinct from that seen in AML samples with a normal karyotype. The results of our studies are consistent with a model of tumor suppression mediated by haploinsufficiency of critical genes in del(9q) AML.
9号染色体长臂缺失（del(9q)）是急性髓系白血病（AML）中反复出现的染色体畸变，常与t(8;21)相关。受del(9q)影响的关键基因产物尚不清楚，但可能在白血病发生过程中与由t(8;21)产生的AML1/ETO融合基因协同作用。在43例伴有del(9q)的AML样本中，我们使用高密度微卫星标记将常见缺失区域（CDR）界定为小于2.4 Mb。我们在所检测的任何位点均未发现纯合缺失。CDR包含7个已知基因，即FRMD3、UBQLN1、GKAP42、KIF27、HNRPK、SLC28A3和NTRK2，以及4个新基因，即RASEF、C9orf103、C9orf64和C9orf76。此外，TLE1和TLE4与CDR相邻。我们对所有这些基因的编码区进行了全面的突变分析。在超过一个伴有del(9q)的AML样本中，未发现正常对照中不存在的序列变异。与正常个体经CD34纯化的祖细胞相比，所检测的10个基因中有7个基因的表达在伴有del(9q)的AML中显著下调，这一模式与核型正常的AML样本不同。我们的研究结果与del(9q) AML中关键基因单倍体不足介导肿瘤抑制的模型一致。
