An erythroid differentiation signature predicts response to lenalidomide in myelodysplastic syndrome
An erythroid differentiation signature predicts response to lenalidomide in myelodysplastic syndrome
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DOI：
10.1371/journal.pmed.0050035
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发表时间：
2008-02-01
期刊：
影响因子：
15.8
通讯作者：
Raza, Azra
中科院分区：
文献类型：
--
作者：
Ebert, Benjamin L.;Galili, Naomi;Raza, Azra
背景来那度胺是治疗骨髓增生异常综合征（MDS）的一种有效新药，MDS是一种获得性造血系统疾病，其特征是血细胞生成效率低下，易发生白血病。染色体5q间质缺失的患者对来那度胺的反应率较高，但大多数MDS患者缺乏这种缺失。大约25%的无5q缺失的患者也从来那度胺治疗中获益，但这些患者的反应不能通过任何现有的诊断测定来预测。本研究的目的是开发一种方法来预测来那度胺的反应，以避免不必要的毒性，患者不太可能受益于treatment.Methods和FindingsUsing基因表达谱，我们确定了一个分子签名，预测来那度胺的反应。在来自没有5q缺失的MDS患者的一组16个治疗前骨髓穿刺物中定义了该特征，并在一组26个样本中进行了验证。反应特征由一组红细胞特异性基因组成，在反应者中表达降低，表明红细胞分化缺陷是来那度胺反应的基础。与此观察一致，来那度胺治疗促进红系分化的初级造血祖细胞生长在vitro. ConclusionsThese研究表明，来那度胺反应的患者有一个缺陷，红系分化，并建议一个战略的临床试验，以预测患者最有可能响应药物。这些实验进一步表明，来那度胺的疗效可能是由于其诱导红细胞分化的能力，来那度胺在MDS中的作用机制尚不清楚。
BackgroundLenalidomide is an effective new agent for the treatment of patients with myelodysplastic syndrome (MDS), an acquired hematopoietic disorder characterized by ineffective blood cell production and a predisposition to the development of leukemia. Patients with an interstitial deletion of Chromosome 5q have a high rate of response to lenalidomide, but most MDS patients lack this deletion. Approximately 25% of patients without 5q deletions also benefit from lenalidomide therapy, but response in these patients cannot be predicted by any currently available diagnostic assays. The aim of this study was to develop a method to predict lenalidomide response in order to avoid unnecessary toxicity in patients unlikely to benefit from treatment.Methods and FindingsUsing gene expression profiling, we identified a molecular signature that predicts lenalidomide response. The signature was defined in a set of 16 pretreatment bone marrow aspirates from MDS patients without 5q deletions, and validated in an independent set of 26 samples. The response signature consisted of a cohesive set of erythroid-specific genes with decreased expression in responders, suggesting that a defect in erythroid differentiation underlies lenalidomide response. Consistent with this observation, treatment with lenalidomide promoted erythroid differentiation of primary hematopoietic progenitor cells grown in vitro.ConclusionsThese studies indicate that lenalidomide-responsive patients have a defect in erythroid differentiation, and suggest a strategy for a clinical test to predict patients most likely to respond to the drug. The experiments further suggest that the efficacy of lenalidomide, whose mechanism of action in MDS is unknown, may be due to its ability to induce erythroid differentiation.