In vivo response to methotrexate forecasts outcome of acute lymphoblastic leukemia and has a distinct gene expression profile.
In vivo response to methotrexate forecasts outcome of acute lymphoblastic leukemia and has a distinct gene expression profile.
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DOI：
10.1371/journal.pmed.0050083
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发表时间：
2008-04-15
期刊：
影响因子：
15.8
通讯作者：
Evans WE
中科院分区：
文献类型：
--
作者：
Sorich MJ;Pottier N;Pei D;Yang W;Kager L;Stocco G;Cheng C;Panetta JC;Pui CH;Relling MV;Cheok MH;Evans WE
儿童急性淋巴细胞白血病（ALL）是儿童中最常见的癌症，现在大约80%的患者可以治愈。然而，耐药性是ALL患儿治疗失败的主要原因。广泛用于治疗多种人类癌症的药物甲氨蝶呤（MTX），基本上被用于全世界所有新诊断的all的治疗方案中。尽管MTX已被广泛研究多年，但对原发癌细胞（包括白血病细胞）的从头耐药机制知之甚少。这种知识的缺乏部分是由于现有的体外方法不够可靠，无法评估原发性ALL细胞的甲氨蝶呤耐药性。因此，我们测量了MTX的体内抗白血病作用，并鉴定了MTX反应良好与不良患者中表达差异显著的基因。我们对293名新诊断的儿童进行体内MTX治疗（1 g/m2）后循环白血病细胞减少的测量，以阐明MTX抗白血病作用的患者间差异。为了确定这些影响的基因组决定因素，我们对161名新诊断的儿童（1-18岁）原发性ALL细胞的基因表达进行了全基因组评估。我们鉴定了48个基因和两个cDNA克隆，它们的表达与MTX体内初始治疗后循环白血病细胞的减少显著相关。这一发现在一个独立的ALL患儿队列中得到了验证。此外，这种初始MTX体内反应和相关基因表达模式的测量可预测长期无病生存（p < 0.001, p = 0.02）。总之，这些数据为MTX耐药的基因组基础和MTX反应的患者间差异提供了新的见解，指出了克服儿童ALL MTX耐药的新策略。试验注册：Total XV，治疗新诊断的急性淋巴细胞白血病患者，http://www.ClinicalTrials.gov (NCT00137111)；Total XIIIBH，基于抗代谢物的诱导加大剂量MTX巩固治疗新诊断的中度或高风险儿童急性淋巴细胞白血病的III期随机研究（NCI-T93-0101D）；Total XIIIBL，基于抗代谢物的诱导加大剂量MTX巩固治疗新诊断的儿童急性淋巴细胞白血病治疗失败风险较低的III期随机研究（NCI-T93-0103D）。William Evans和他的同事研究了甲氨蝶呤耐药性的基因组决定因素，以及新诊断的儿童急性淋巴细胞白血病患者甲氨蝶呤反应的患者间差异。在美国，每年大约有1万名儿童患上癌症。急性淋巴细胞白血病（ALL）是一种进展迅速的血癌，占这些儿童癌症的四分之一。正常情况下，骨髓中的细胞（骨骼内的海绵状物质）会发育成淋巴细胞（对抗感染的白细胞）、红细胞（在体内携带氧气）、血小板（防止过度出血）和粒细胞（另一种白细胞）。然而，在ALL中，未成熟淋巴细胞（淋巴母细胞）的遗传变化意味着这些细胞不受控制地分裂而不能成熟。最终，骨髓中充满了这些异常细胞，再也不能产生健康的血细胞。因此，患有ALL的儿童无法抵抗感染。他们也容易受伤和流血，因为他们没有足够的红细胞，他们经常抱怨疲劳和虚弱。使用现代化疗方案（药物组合杀死快速分裂的癌细胞，但留下体内正常的、不分裂的细胞，基本上毫发无损），超过80%的ALL患儿至少活了5年。尽管存活率很高，但仍有一些患者因为癌细胞对一种或多种化疗药物产生耐药性而死亡。对于某些药物，已知ALL细胞的遗传特征使它们具有耐药性。不幸的是，对于为什么一些ALL细胞对甲氨蝶呤具有耐药性知之甚少，甲氨蝶呤是大多数新诊断的ALL治疗方案的组成部分。甲氨蝶呤通过干扰DNA的合成和修复来杀死分裂的细胞。癌细胞对甲氨蝶呤产生抗药性的原因有很多——例如，它们可能已经发生了基因变化，阻止了药物进入它们体内。在制定治疗甲氨蝶呤耐药ALL的新策略之前，需要更好地了解这些耐药机制。在这项研究中，研究人员确定了新诊断患者对甲氨蝶呤的反应，并研究了ALL细胞中与甲氨蝶呤良好和不良反应相关的基因表达模式。研究人员测量了近300名新诊断为ALL的患者在接受甲氨蝶呤首次治疗后循环白血病细胞的减少。他们还使用“微阵列”分析来研究治疗前从161名患者骨髓中提取的淋巴细胞样本中的基因表达模式。他们发现50个基因的表达与甲氨蝶呤治疗后循环白血病细胞的减少显著相关（这一结果在一组独立的患者中得到证实）。在这些基因中，29个基因在甲氨蝶呤反应较差的患者中的表达高于反应良好的患者。一项“全局分析测试”检查了与甲氨蝶呤反应相关的不同细胞途径的基因表达谱，发现核苷酸生物合成途径（DNA合成和细胞增殖所必需的）与甲氨蝶呤反应之间存在显著关联。最后，具有最佳甲氨蝶呤反应和50个基因表达谱表明良好反应的患者在5年后比具有最差甲氨蝶呤反应和不良反应基因表达谱的患者更有可能存活。这些发现为新诊断的儿童ALL甲氨蝶呤耐药的遗传基础提供了重要的新见解，并开始解释为什么一些患者对这种药物没有反应。他们还表明，在第一次服用甲氨蝶呤后不久，循环白血病细胞的减少和特定的基因表达谱都预示着患者的长期生存。这些发现也提出了调节对甲氨蝶呤敏感性的新方法。在不良反应者中比在良好反应者中表达更高的基因表达下调可能会改善患者对甲氨蝶呤的反应。另一种选择是，有可能找到方法来增加甲氨蝶呤不良应答者中表达不足的基因的表达，从而改善至少一些对当前化疗方案没有反应的ALL儿童的前景。请通过本摘要的在线版本http://dx.doi.org/10.1371/journal.pmed.0050083访问这些网站。•美国国家癌症研究所为患者和护理人员提供关于儿童ALL及其治疗信息的情况说明书（英语和西班牙语）•英国慈善机构Cancerbackup为患者和护理人员提供有关儿童ALL和甲氨蝶呤的信息•美国白血病和淋巴瘤协会也为患者和护理人员提供有关ALL的信息•儿童癌症和白血病小组（英国慈善机构）为患有癌症和白血病的儿童提供信息•MedlinePlus提供有关甲氨蝶呤的更多信息（英文和西班牙文）
Childhood acute lymphoblastic leukemia (ALL) is the most common cancer in children, and can now be cured in approximately 80% of patients. Nevertheless, drug resistance is the major cause of treatment failure in children with ALL. The drug methotrexate (MTX), which is widely used to treat many human cancers, is used in essentially all treatment protocols worldwide for newly diagnosed ALL. Although MTX has been extensively studied for many years, relatively little is known about mechanisms of de novo resistance in primary cancer cells, including leukemia cells. This lack of knowledge is due in part to the fact that existing in vitro methods are not sufficiently reliable to permit assessment of MTX resistance in primary ALL cells. Therefore, we measured the in vivo antileukemic effects of MTX and identified genes whose expression differed significantly in patients with a good versus poor response to MTX. We utilized measures of decreased circulating leukemia cells of 293 newly diagnosed children after initial “up-front” in vivo MTX treatment (1 g/m2) to elucidate interpatient differences in the antileukemic effects of MTX. To identify genomic determinants of these effects, we performed a genome-wide assessment of gene expression in primary ALL cells from 161 of these newly diagnosed children (1–18 y). We identified 48 genes and two cDNA clones whose expression was significantly related to the reduction of circulating leukemia cells after initial in vivo treatment with MTX. This finding was validated in an independent cohort of children with ALL. Furthermore, this measure of initial MTX in vivo response and the associated gene expression pattern were predictive of long-term disease-free survival (p < 0.001, p = 0.02). Together, these data provide new insights into the genomic basis of MTX resistance and interpatient differences in MTX response, pointing to new strategies to overcome MTX resistance in childhood ALL. Trial registrations: Total XV, Therapy for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia, http://www.ClinicalTrials.gov (NCT00137111); Total XIIIBH, Phase III Randomized Study of Antimetabolite-Based Induction plus High-Dose MTX Consolidation for Newly Diagnosed Pediatric Acute Lymphocytic Leukemia at Intermediate or High Risk of Treatment Failure (NCI-T93-0101D); Total XIIIBL, Phase III Randomized Study of Antimetabolite-Based Induction plus High-Dose MTX Consolidation for Newly Diagnosed Pediatric Acute Lymphocytic Leukemia at Lower Risk of Treatment Failure (NCI-T93-0103D). William Evans and colleagues investigate the genomic determinants of methotrexate resistance and interpatient differences in methotrexate response in patients newly diagnosed with childhood acute lymphoblastic leukemia. Every year about 10,000 children develop cancer in the US. Acute lymphoblastic leukemia (ALL), a rapidly progressing blood cancer, accounts for a quarter of these childhood cancers. Normally, cells in the bone marrow (the spongy material inside bones) develop into lymphocytes (white blood cells that fight infections), red blood cells (which carry oxygen round the body), platelets (which prevent excessive bleeding), and granulocytes (another type of white blood cell). However, in ALL, genetic changes in immature lymphocytes (lymphoblasts) mean that these cells divide uncontrollably and fail to mature. Eventually, the bone marrow fills up with these abnormal cells and can no longer make healthy blood cells. As a result, children with ALL cannot fight infections. They also bruise and bleed easily and, because they do not have enough red blood cells, they often complain of tiredness and weakness. With modern chemotherapy protocols (combinations of drugs that kill the fast-dividing cancer cells but leave the normal, nondividing cells in the body largely unscathed), more than 80% of children with ALL live for at least 5 years. Although this survival rate is good, some patients still die because their cancer cells are resistant to one or more chemotherapy drugs. For some drugs, the genetic characteristics of the ALL cells that make them resistant are known. Unfortunately, little is known about why some ALL cells are resistant to methotrexate, a component of most treatment protocols for newly diagnosed ALL. Methotrexate kills dividing cells by interfering with DNA synthesis and repair. Cancer cells can be resistant to methotrexate for many reasons—they may have acquired genetic changes that stop the drug from entering them, for example. These resistance mechanisms need to be understood better before new strategies can be developed for the treatment of methotrexate-resistant ALL. In this study, the researchers have determined the response of newly diagnosed patients to methotrexate and have investigated the gene expression patterns in ALL cells that correlate with good and bad responses to methotrexate. The researchers measured the reduction in circulating leukemia cells that followed the first treatment with methotrexate of nearly 300 patients with newly diagnosed ALL. They also used “microarray” analysis to investigate the gene expression patterns in lymphoblast samples taken from the bone marrow of 161 patients before treatment. They found that the expression of 50 genes was significantly related to the reduction in circulating leukemia cells after methotrexate treatment (a result confirmed in an independent group of patients). Of these genes, the expression of 29 was higher in patients who responded poorly to methotrexate than in patients who responded well. A “global analysis test,” which examined the gene expression profile of different cellular pathways in relation to the methotrexate response, found a significant association between the nucleotide biosynthesis pathway (which is needed for DNA synthesis and cellular proliferation) and the methotrexate response. Finally, patients with the best methotrexate response and the 50-gene expression profile indicative of a good response were more likely to be alive after 5 years than patients with the worst methotrexate response and the poor-response gene expression profile. These findings provide important new insights into the genetic basis of methotrexate resistance in newly diagnosed childhood ALL and begin to explain why some patients fail to respond to this drug. They also show that the reduction in circulating leukemic cells shortly after the first methotrexate dose and a specific gene expression profile both predict the long-term survival of patients. These findings also suggest new ways to modulate sensitivity to methotrexate. Down-regulation of the expression of the genes that are expressed more highly in poor responders than in good responders might improve patient responses to methotrexate. Alternatively, it might be possible to find ways to increase the expression of the genes that are underexpressed in methotrexate poor responders and so improve the outlook for at least some of the children with ALL who fail to respond to current chemotherapy protocols. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050083. • The US National Cancer Institute provides a fact sheet for patients and caregivers about ALL in children and information about its treatment(in English and Spanish) • The UK charity Cancerbackup provides information for patients and caregivers on ALL in children and on methotrexate • The US Leukemia and Lymphoma Society also provides information for patients and caregivers about ALL • The Children's Cancer and Leukaemia Group (a UK charity) provides information for children with cancer and their families • MedlinePlus provides additional information about methotrexate (in English and Spanish)
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影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
56.9
作者：
Golub, TR;Slonim, DK;Lander, ES
通讯作者：
Lander, ES
影响因子：
15.9
作者：
CHABNER, BA;ALLEGRA, CJ;JOLIVET, J
通讯作者：
JOLIVET, J
DOI：
10.1016/s0925-4439(02)00079-0
发表时间：
2002-07-18
影响因子：
6.2
作者：
Banerjee, D;Mayer-Kuckuk, P;Bertino, JR
通讯作者：
Bertino, JR
影响因子：
30.8
作者：
Cheok, MH;Yang, WL;Evans, WE
通讯作者：
Evans, WE