Molecular Biology Unit, Department of Hematology/Oncology Seràgnoli, University of Bologna, Via Massarenti 9, Bologna, Italy.
Haematologica. 2010 Oct;95(10):1683-90. doi: 10.3324/haematol.2009.020792. Epub 2010 Jun 9.
Recently, in genome-wide analyses of DNA copy number abnormalities using single nucleotide polymorphism microarrays, genetic alterations targeting PAX5 were identified in over 30% of pediatric patients with acute lymphoblastic leukemia. So far the occurrence of PAX5 alterations and their clinical correlation have not been investigated in adults with BCR-ABL1-positive acute lymphoblastic leukemia.
The aim of this study was to characterize the rearrangements on 9p involving PAX5 and their clinical significance in adults with BCR-ABL1-positive acute lymphoblastic leukemia. Eighty-nine adults with de novo BCR-ABL1-positive acute lymphoblastic leukemia were enrolled into institutional (n=15) or GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) (n=74) clinical trials and, after obtaining informed consent, their genome was analyzed by single nucleotide polymorphism arrays (Affymetrix 250K NspI and SNP 6.0), genomic polymerase chain reaction analysis and re-sequencing.
PAX5 genomic deletions were identified in 29 patients (33%) with the extent of deletions ranging from a complete loss of chromosome 9 to the loss of a subset of exons. In contrast to BCR-ABL1-negative acute lymphoblastic leukemia, no point mutations were found, suggesting that deletions are the main mechanism of inactivation of PAX5 in BCR-ABL1-positive acute lymphoblastic leukemia. The deletions were predicted to result in PAX5 haploinsufficiency or expression of PAX5 isoforms with impaired DNA-binding. Deletions of PAX5 were not significantly correlated with overall survival, disease-free survival or cumulative incidence of relapse, suggesting that PAX5 deletions are not associated with outcome.
PAX5 deletions are frequent in adult BCR-ABL1-positive acute lymphoblastic leukemia and are not associated with a poor outcome.
最近，在使用单核苷酸多态性微阵列进行全基因组 DNA 拷贝数异常分析时，在超过 30%的儿童急性淋巴细胞白血病患者中发现了靶向 PAX5 的基因改变。迄今为止，尚未在 BCR-ABL1 阳性急性淋巴细胞白血病的成人中研究 PAX5 改变的发生及其临床相关性。
本研究旨在描述涉及 PAX5 的 9p 重排及其在 BCR-ABL1 阳性急性淋巴细胞白血病成人中的临床意义。89 例初发 BCR-ABL1 阳性急性淋巴细胞白血病成人入组机构（n=15）或 GIMEMA（Gruppo Italiano Malattie EMatologiche dell'Adulto）（n=74）临床试验，并在获得知情同意后，采用单核苷酸多态性阵列（Affymetrix 250K NspI 和 SNP 6.0）、基因组聚合酶链反应分析和重测序分析其基因组。
在 29 例（33%）患者中发现 PAX5 基因组缺失，缺失范围从整条 9 号染色体缺失到部分外显子缺失不等。与 BCR-ABL1 阴性急性淋巴细胞白血病不同，未发现点突变，提示缺失是 BCR-ABL1 阳性急性淋巴细胞白血病中 PAX5 失活的主要机制。这些缺失预计会导致 PAX5 单倍不足或表达具有受损 DNA 结合能力的 PAX5 同工型。PAX5 缺失与总生存、无病生存或累积复发率无显著相关性，提示 PAX5 缺失与结局无关。
PAX5 缺失在成人 BCR-ABL1 阳性急性淋巴细胞白血病中很常见，与不良结局无关。
