Hematologic Malignancy Division, H Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
Expert Rev Hematol. 2011 Feb;4(1):61-9. doi: 10.1586/ehm.11.2.
The 5q- syndrome is a unique subtype of myelodysplastic syndromes typified by a relatively indolent course and responsiveness to lenalidomide. Here, we review the salient biologic features of this disease. Hemizygous deletion of a segment of chromosome 5q is believed to be the disease-initiating event. Recent molecular techniques have isolated the common deleted region and characterized key candidate genes contributing to the disease phenotype. Gene-specific RNA interference strategies revealed that haplo-insufficiency for the RPS14 gene, which encodes a ribosomal protein, is a critical effector of the p53-dependent erythroid hypoplasia and apoptotic loss of erythroid precursors. Disease-specific sensitivity to lenalidomide results from the drug's inhibitory effect on two haplodeficient phosphatases, PP2Acα and CDC25c, which are coregulators of the G(2)/M checkpoint. Hyperphosphorylation of MDM2, as a result of inhibition of PP2A phosphatase activity, stabilizes MDM2, permitting p53 degradation and transition to G(2) arrest and clonal suppression. With the emerging data elucidating the pathogenesis of the 5q- syndrome and the success of clinical trials, a cohesive story connecting the biology and pharmacology associated with this subtype of myelodysplastic syndromes has emerged.
5q- 综合征是一种独特的骨髓增生异常综合征亚型，其特点是病程相对惰性且对来那度胺有反应。在这里，我们回顾了这种疾病的显著生物学特征。人们认为，染色体 5q 片段的杂合性缺失是疾病的起始事件。最近的分子技术已经分离出常见的缺失区域，并描述了导致疾病表型的关键候选基因。基因特异性 RNA 干扰策略表明，编码核糖体蛋白的 RPS14 基因的单倍体不足是 p53 依赖性红细胞发育不全和红细胞前体细胞凋亡丢失的关键效应因子。对来那度胺的特异性敏感性源于该药物对两种单倍体缺乏磷酸酶（PP2Acα 和 CDC25c）的抑制作用，这两种磷酸酶是 G(2)/M 检查点的核心调节剂。由于 PP2A 磷酸酶活性的抑制，MDM2 的过度磷酸化稳定了 MDM2，从而允许 p53 降解并过渡到 G(2) 停滞和克隆抑制。随着阐明 5q- 综合征发病机制的新兴数据和临床试验的成功，与这种骨髓增生异常综合征亚型相关的生物学和药理学之间的联系已经形成。
