Galili Naomi, Cerny Jan, Raza Azra
Radhey Khanna MDS Center, Division of Hematology, University of Massachusetts Medical Center, 364 Plantation Street, Worcester, MA 01605, USA.
Curr Treat Options Oncol. 2007 Apr;8(2):117-28. doi: 10.1007/s11864-007-0017-1.
The heterogeneity of myelodysplastic syndromes (MDS) has driven the search for unifying biologic and clinical features that would stratify patients into distinct prognostic and therapeutic subgroups. Cytogenetics has been shown to impact the course of myelodysplasia. Despite the presence of non-random cytogenetic abnormalities in approximately 50% of MDS patients, it is significant that only a proportion of metaphases may contain the abnormality. Clonality studies however show that the karyotypically normal metaphases are still part of the MDS clone. This would suggest that the chromosomal abnormality may not be the initiating lesion in MDS, and that the gross karyotypic changes represent clonal evolution in a genetically unstable population. Yet, as will be described below, specific cytogenetic abnormalities are associated with clinically and biologically distinct forms of the disease, most notable in the response of del(5q) patients to lenalidomide. One possible explanation for the appearance of non-random mutational events could relate to the interaction of MDS cells with their microenvironment. Whatever the initiating lesion in the MDS stem cell, the end result is a clonal expansion where the marrow becomes populated by the monoclonal progeny of this cell. Interaction of these cells with a microenvironment which has been shown to be rich in pro-apoptotic cytokines such as tumor necrosis factor alpha (TNFa), leads to increased genetic instability. Hypoxia mediated decrease in DNA repair enzymes could further accelerate mutational events culminating in accumulation of multiple chromosomal abnormalities. Some of these chromosomal changes are associated with increased sensitivity to specific drugs. Lenalidomide has shown a high degree of efficacy in MDS patients with del(5q), although the target for the drug is unknown since a small but significant subset of MDS patients without del(5q) abnormality also respond to the drug. In contrast, the molecular target for imatinib mesylate is known; mutations in tyrosine kinase receptor family of genes found in patients with t(5;12) and del(4q12) make these individuals sensitive to the drug. Patients with isolated trisomy 8 have an immune component to the disease phenotype which can be targeted by cyclosporine and or anti-thymocyte globulin (ATG), especially in the presence of a PNH (paroxysmal nocturnal hemoglobinurea) clone. In the absence of these specific cytogenetic abnormalities described above, the two FDA approved hypomethylating agents 5 azacytidine and decitabine should be considered as therapeutic alternatives.
骨髓增生异常综合征（MDS）的异质性促使人们寻找统一的生物学和临床特征，以便将患者分为不同的预后和治疗亚组。细胞遗传学已被证明会影响骨髓增生异常的病程。尽管约50%的MDS患者存在非随机的细胞遗传学异常，但重要的是只有一部分中期细胞可能含有该异常。然而，克隆性研究表明，核型正常的中期细胞仍是MDS克隆的一部分。这表明染色体异常可能不是MDS的起始病变，且总体核型变化代表了基因不稳定群体中的克隆进化。然而，如下所述，特定的细胞遗传学异常与该疾病在临床和生物学上的不同形式相关，最显著的是del(5q)患者对来那度胺的反应。非随机突变事件出现的一种可能解释可能与MDS细胞与其微环境的相互作用有关。无论MDS干细胞中的起始病变是什么，最终结果都是克隆性扩增，骨髓中充满了该细胞的单克隆后代。这些细胞与已被证明富含促凋亡细胞因子（如肿瘤坏死因子α（TNFα））的微环境相互作用，会导致基因不稳定性增加。缺氧介导的DNA修复酶减少可能会进一步加速突变事件，最终导致多个染色体异常的积累。其中一些染色体变化与对特定药物的敏感性增加有关。来那度胺在伴有del(5q)的MDS患者中显示出高度疗效，尽管该药物的靶点尚不清楚，因为一小部分但数量可观的无del(5q)异常的MDS患者也对该药物有反应。相比之下，甲磺酸伊马替尼的分子靶点是已知的；在t(5;12)和del(4q12)患者中发现的酪氨酸激酶受体家族基因的突变使这些个体对该药物敏感。孤立性8号染色体三体的患者疾病表型具有免疫成分，可被环孢素和/或抗胸腺细胞球蛋白（ATG）靶向，特别是在存在阵发性睡眠性血红蛋白尿（PNH）克隆的情况下。在不存在上述特定细胞遗传学异常的情况下，两种美国食品药品监督管理局（FDA）批准的低甲基化药物5-氮杂胞苷和地西他滨应被视为治疗选择。
