Fadlelmola Faisal M, Zhou Minglong, de Leeuw Ronald J, Dosanjh Nirpjit S, Harmer Karynn, Huntsman David, Lam Wan L, Banerjee Diponkar
Centre for Translational and Applied Genomics (CTAG), Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, Vancouver Cancer Centre, Vancouver, BC, V5Z 4E6, Canada.
Mol Cancer. 2008 Jan 7;7:2. doi: 10.1186/1476-4598-7-2.
Hodgkin lymphoma (HL) and Anaplastic Large Cell Lymphoma (ALCL), are forms of malignant lymphoma defined by unique morphologic, immunophenotypic, genotypic, and clinical characteristics, but both overexpress CD30. We used sub-megabase resolution tiling (SMRT) array-based comparative genomic hybridization to screen HL-derived cell lines (KMH2 and L428) and ALCL cell lines (DEL and SR-786) in order to identify disease-associated gene copy number gains and losses.
Significant copy number gains and losses were observed on several chromosomes in all four cell lines. Assessment of copy number alterations with 26,819 DNA segments identified an average of 20 genetic alterations. Of the recurrent minimally altered regions identified, 11 (55%) were within previously published regions of chromosomal alterations in HL and ALCL cell lines while 9 (45%) were novel alterations not previously reported. HL cell lines L428 and KMH2 shared gains in chromosome cytobands 2q23.1-q24.2, 7q32.2-q36.3, 9p21.3-p13.3, 12q13.13-q14.1, and losses in 13q12.13-q12.3, and 18q21.32-q23. ALCL cell lines SR-786 and DEL, showed gains in cytobands 5p15.32-p14.3, 20p12.3-q13.11, and 20q13.2-q13.32. Both pairs of HL and ALCL cell lines showed losses in 18q21.32-18q23.
This study is considered to be the first one describing HL and ALCL cell line genomes at sub-megabase resolution. This high-resolution analysis allowed us to propose novel candidate target genes that could potentially contribute to the pathogenesis of HL and ALCL. FISH was used to confirm the amplification of all three isoforms of the trypsin gene (PRSS1/PRSS2/PRSS3) in KMH2 and L428 (HL) and DEL (ALCL) cell lines. These are novel findings that have not been previously reported in the lymphoma literature, and opens up an entirely new area of research that has not been previously associated with lymphoma biology. The findings raise interesting possibilities about the role of signaling pathways triggered by membrane associated serine proteases in HL and aggressive NHL, similar to those described in epithelial tumors.
霍奇金淋巴瘤（HL）和间变性大细胞淋巴瘤（ALCL）是恶性淋巴瘤的两种形式，由独特的形态学、免疫表型、基因型和临床特征定义，但二者均过度表达CD30。我们使用基于亚兆碱基分辨率平铺（SMRT）阵列的比较基因组杂交技术，对HL来源的细胞系（KMH2和L428）和ALCL细胞系（DEL和SR - 786）进行筛选，以确定与疾病相关的基因拷贝数增加和减少情况。
在所有四个细胞系的几条染色体上均观察到显著的拷贝数增加和减少。用26,819个DNA片段评估拷贝数改变，平均鉴定出20个基因改变。在鉴定出的反复出现的微小改变区域中，11个（55%）位于HL和ALCL细胞系先前已发表的染色体改变区域内，而9个（45%）是先前未报道的新改变。HL细胞系L428和KMH2在染色体细胞带2q23.1 - q24.2、7q32.2 - q36.3、9p21.3 - p13.3、12q13.13 - q14.1有拷贝数增加，在13q12.13 - q12.3和18q21.32 - q23有拷贝数减少。ALCL细胞系SR - 786和DEL在细胞带5p15.32 - p14.3、20p12.3 - q13.11和20q13.2 - q13.32有拷贝数增加。HL和ALCL细胞系这两对均在18q21.32 - 18q23有拷贝数减少。
本研究被认为是第一项以亚兆碱基分辨率描述HL和ALCL细胞系基因组的研究。这种高分辨率分析使我们能够提出可能有助于HL和ALCL发病机制的新候选靶基因。使用荧光原位杂交（FISH）技术证实了胰蛋白酶基因（PRSS1/PRSS2/PRSS3）的所有三种异构体在KMH2和L428（HL）以及DEL（ALCL）细胞系中的扩增。这些是淋巴瘤文献中先前未报道的新发现，并开辟了一个以前与淋巴瘤生物学无关的全新研究领域。这些发现提出了关于膜相关丝氨酸蛋白酶触发的信号通路在HL和侵袭性非霍奇金淋巴瘤中的作用的有趣可能性，类似于上皮肿瘤中所描述的情况。
