Alterations of the Cell-Cycle Inhibitors p27KIP1 and p16INK4a Are Frequent in Blastic Plasmacytoid Dendritic Cell Neoplasms
Alterations of the Cell-Cycle Inhibitors p27KIP1 and p16INK4a Are Frequent in Blastic Plasmacytoid Dendritic Cell Neoplasms
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DOI：
10.1038/jid.2009.369
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发表时间：
2010-04-01
影响因子：
6.5
通讯作者：
Cerroni, Lorenzo
中科院分区：
文献类型：
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作者：
Wiesner, Thomas;Obenauf, Anna C.;Cerroni, Lorenzo
母细胞浆细胞样树突状细胞肿瘤（BPDCN）是一种罕见的，临床上具有侵袭性的恶性肿瘤，中位生存期为12-14个月。为了确定致病相关的基因组畸变和治疗的分子靶点，我们使用基于高分辨率阵列的比较基因组杂交和免疫染色分析了14例患者的皮肤活检样本。9、12、13和15号染色体的丢失率最高。CDKN 1B基因座的丢失是最常见的发现，在64%的肿瘤中检测到。在所有的情况下，但一个剂量依赖性单倍不足的细胞周期抑制剂p27（KIP 1），编码的CDKN 1B，弱表达在肿瘤细胞的细胞核。CDKN 2A-ARF-CDKN 2B位点的丢失发生在50%的患者中，并且在一个病例中确定了明显的双等位基因丢失。由CDKN 2A编码的细胞周期抑制剂p16（INK 4a）在肿瘤细胞中不表达，表明功能完全丧失。在43%的肿瘤中观察到13号染色体缺失，包括RB 1基因。这些结果表明，细胞周期检查点控制蛋白p27（KIP 1），p16（INK 4a）和RB 1的改变可能会在BPDCN的恶性转化中产生深远的影响。阐明受影响的途径可能会指导专门为这种侵袭性疾病实体设计的新治疗方法的开发。
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, clinically aggressive malignancy with a median survival of 12-14 months. To identify pathogenetic relevant genomic aberrations and molecular targets for therapy, we analyzed skin biopsy samples obtained from 14 patients using high-resolution array-based comparative genomic hybridization and immunostaining. Losses of chromosomes 9, 12, 13, and 15 were detected most frequently. Loss of the CDKN1B locus was the most common finding and was detected in 64% of tumors. In all but one case, the dose-dependent haploinsufficient cell-cycle inhibitor p27(KIP1), encoded by CDKN1B, was weakly expressed in the nuclei of tumor cells. Losses of the CDKN2A-ARF-CDKN2B locus occurred in 50% of patients, and in one case a distinct biallelic loss was identified. The cell-cycle inhibitor p16(INK4a), which is encoded by CDKN2A, was not expressed in tumor cells, suggesting a complete loss of function. Loss of chromosome 13, including the RB1gene, was observed in 43% of tumors. These results imply that alterations of the cell-cycle checkpoint controlling proteins p27(KIP1), p16(INK4a), and RB1 may exert a profound effect in malignant transformation in BPDCN. The elucidation of the affected pathways may guide the development of new treatments specifically designed for this aggressive disease entity.