The gene expression signature of relapse in paediatric acute lymphoblastic leukaemia: implications for mechanisms of therapy failure
The gene expression signature of relapse in paediatric acute lymphoblastic leukaemia: implications for mechanisms of therapy failure
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DOI：
10.1111/j.1365-2141.2005.05785.x
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发表时间：
2005-11-01
影响因子：
6.5
通讯作者：
Kees, UR
中科院分区：
文献类型：
--
作者：
Beesley, AH;Cummings, AJ;Kees, UR
尽管儿童急性淋巴细胞白血病（ALL）的治疗有了显著的改善，但复发患者的预后仍然很差。本研究的目的是生成复发ALL的转录谱，以增加我们对治疗失败机制的理解。从诊断和复发时取自相同患者的11对冷冻保存的前B ALL骨髓标本中提取RNA，并使用HG-U133 A微阵列进行分析。复发标本过表达与细胞生长和增殖有关的基因，与其侵袭性表型一致。当在72个前B ALL和T-ALL的独立样本中进行测试时，所识别的基因可以成功区分任一谱系中的诊断和复发，这表明存在两者共同的复发机制。这些基因具有与肿瘤发生、耐药和转移相关的功能，但与经典的多药耐药途径无关。在诊断时增加的顶级基因（BSG）的表达与不良结局显著相关。包括19 p13在内的几个染色体位点被确定为复发性ALL中异常基因表达的潜在热点。我们的研究结果为耐药性和微环境之间的联系提供了证据，而这种联系以前只在实体肿瘤生物学的背景下被考虑过。
Despite significant improvements in the treatment of childhood acute lymphoblastic leukaemia (ALL), the prognosis for relapsing patients remains poor. The aim of this study was to generate a transcriptional profile of relapsed ALL to increase our understanding of the mechanisms involved in therapy failure. RNA was extracted from 11 pairs of cryopreserved pre-B ALL bone marrow specimens taken from the same patients at diagnosis and relapse, and analysed using HG-U133A microarrays. Relapse specimens overexpressed genes that are involved with cell growth and proliferation, in keeping with their aggressive phenotype. When tested in 72 independent specimens of pre-B ALL and T-ALL, the identified genes could successfully differentiate between diagnosis and relapse in either lineage, indicating the existence of relapse mechanisms common to both. These genes have functions relevant for oncogenesis, drug resistance and metastasis, but are not related to classical multidrug-resistance pathways. Increased expression of the top-ranked gene (BSG) at diagnosis was significantly associated with adverse outcome. Several chromosomal loci, including 19p13, were identified as potential hotspots for aberrant gene expression in relapsed ALL. Our results provide evidence for a link between drug resistance and the microenvironment that has previously only been considered in the context of solid tumour biology.