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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Lenalidomide inhibits the malignant clone and up-regulates the SPARC gene mapping to the commonly deleted region in 5q- syndrome patients
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Lenalidomide inhibits the malignant clone and up-regulates the SPARC gene mapping to the commonly deleted region in 5q- syndrome patients

机译：来那度胺抑制5q综合征患者的恶性克隆并上调SPARC基因定位到通常缺失的区域

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摘要

Myelodysplastic syndromes (MDSs) are a group of hematopoietic stem cell disorders characterized by ineffective hematopoiesis and peripheral blood cytopenias. Lenalidomide has dramatic therapeutic effects in patients with low-risk MDS and a chromosome 5q31 deletion, resulting in complete cytogenetic remission in > 60% of patients. The molecular basis of this remarkable drug response is unknown. To gain insight into the molecular targets of lenalidomide we investigated its in vitro effects on growth, maturation, and global gene expression in isolated erythroblast cultures from MDS patients with del(5)(q31). Lenalidomide inhibited growth of differentiating del(5q) erythroblasts but did not affect cytogenetically normal cells. Moreover, lenalidomide significantly influenced the pattern of gene expression in del(5q) intermediate erythroblasts, with the VSIG4. PPIC, TPBG, activin A, and SPARC genes up-regulated by > 2-fold in all samples and many genes involved in erythropoiesis, including HBA2, GYPA, and KLF1, down-regulated in most samples. Activin A, one of the most significant differentially expressed genes between lenalidomide-treated cells from MDS patients and healthy controls, has pleiotropic functions, including apoptosis of hematopoietic cells. Up-regulation and increased protein expression of the tumor suppressor gene SPARC is of particular interest because it is antiproliferative, antiadhesive, and antiangiogenic and is located at 5q31-q32, within the commonly deleted region in MDS 5q- syndrome. We conclude that lenalidomide inhibits growth of del(5q) erythroid progenitors and that the up-regulation of SPARC and activin A may underlie the potent effects of lenalidomide in MDS with del(5)(q31). SPARC may play a role in the pathogenesis of the 5q- syndrome.
机译：骨髓增生异常综合症（MDS）是一组造血干细胞疾病，其特征是造血功能不全和外周血细胞减少症。来那度胺对低危MDS和5q31染色体缺失的患者具有显着的治疗作用，导致> 60％的患者完全细胞遗传学缓解。这种显着的药物反应的分子基础是未知的。为了深入了解来那度胺的分子靶标，我们研究了其对del（5）（q31）MDS患者隔离的成红细胞培养物中生长，成熟和全局基因表达的体外影响。来那度胺抑制分化的del（5q）成红细胞的生长，但不影响细胞遗传学正常细胞。此外，来那度胺与VSIG4一起显着影响del（5q）中间成红细胞中基因表达的模式。在所有样品中，PPIC，TPBG，激活素A和SPARC基因的表达均被上调了2倍以上，而与红细胞生成有关的许多基因（包括HBA2，GYPA和KLF1）在大多数样品中均被下调。激活素A是来自MDS患者的来那度胺治疗的细胞与健康对照之间最重要的差异表达基因之一，具有多效功能，包括造血细胞的凋亡。抑癌基因SPARC的上调和蛋白质表达的增加特别令人关注，因为它具有抗增殖，抗黏附和抗血管生成作用，位于MDS 5q综合征中通常缺失区域内的5q31-q32处。我们得出的结论是来那度胺会抑制del（5q）红系祖细胞的生长，并且SPARC和激活素A的上调可能是来那度胺在具有del（5）（q31）的MDS中的有效作用的基础。 SPARC可能在5q-综合征的发病机理中起作用。

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