Dysregulated Class I histone deacetylases are indicators of poor prognosis in multiple myeloma
Dysregulated Class I histone deacetylases are indicators of poor prognosis in multiple myeloma
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DOI：
10.4161/15592294.2014.983367
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发表时间：
2014-11-01
期刊：
影响因子：
3.7
通讯作者：
Spencer, Andrew
中科院分区：
文献类型：
--
作者：
Mithraprabhu, Sridurga;Kalff, Anna;Spencer, Andrew
组蛋白去乙酰化酶（HDAC）通过其乙酰化蛋白质的能力来控制基因表达，从而影响多种细胞功能。I类HDAC（HDAC 1 -3和8）和HDAC 6主要在恶性肿瘤中上调，并且它们在一些癌症中的改变的表达具有显著的预后意义。在多发性骨髓瘤（MM）中起关键作用的I类HDAC和HDAC 6的表达和预后结果尚不清楚。本研究假设HDAC在MM中失调，高表达患者的预后明显较差。在遗传异质性人骨髓瘤细胞系（HMCL）和原发性MM中对11种HDAC（I、II和IV类）进行定量PCR，并与正常浆细胞（PC）进行比较。在HMCL中，与正常PC相比，HDAC 1 -3和8（I类）以及HDAC 5和HDAC 10（II类）显著上调。在原发性MM中，与正常PC相比，除HDAC 1和HDAC 11外，所有HDAC的中位表达水平均升高。HDAC 1 -3、HDAC 4、HDAC 6和HDAC 11转录水平较高的患者表现出显著较短的无进展生存期（PFS）。来自一个接受统一治疗的符合移植条件的MM患者队列的骨髓环钻上的HDAC 1和HDAC 6的免疫组织化学染色显示，HDAC 1蛋白在大多数患者中可检测到，较高水平的MM细胞HDAC 1蛋白表达（90%对20% MM细胞阳性）与较短的PFS（P = 0.07）和较短的总生存期（P = 0.003）相关。相反，虽然大多数患者表达HDAC 6，但HDAC 6水平与患者结局之间没有相关性。总之，这些结果表明I类HDAC，特别是HDAC 1的过表达与MM的不良预后相关。
Histone deacetylases (HDAC) control gene expression through their ability to acetylate proteins, thereby influencing a diverse range of cellular functions. Class I HDAC (HDAC1-3 and 8) and HDAC6 are predominantly upregulated in malignancies and their altered expression in some cancers has a significant prognostic implication. The expression and prognostic consequence of dysregulated Class I HDAC and HDAC6, key players in multiple myeloma (MM), are unknown. This study hypothesized that HDAC are dysregulated in MM and patients with high expression have significantly poorer prognostic outcomes. Quantitative PCR for 11 HDAC (Class I, II, and IV) was performed in genetically heterogeneous human myeloma cell lines (HMCL) and primary MM and compared to normal plasma cells (PC). In HMCL, HDAC1-3 and 8 (Class I), and HDAC5 and HDAC10 (Class II) were significantly upregulated compared to normal PC. In primary MM, the median expression level of all of the HDAC, except HDAC1 and HDAC11, were elevated when compared to normal PC. Patients with higher levels of HDAC1-3, HDAC4, HDAC6, and HDAC11 transcripts demonstrated a significantly shorter progression-free survival (PFS). Immunohistochemical staining for HDAC1 and HDAC6 on bone marrow trephines from a uniformly treated cohort of transplant eligible MM patients revealed that HDAC1 protein was detectable in most patients and that higher levels of MM cell HDAC1 protein expression (90 % versus 20 % MM cell positivity) correlated with both shorter PFS (P = 0 .07) and shorter overall survival (P = 0 .003). Conversely, while the majority of patients expressed HDAC6, there was no correlation between HDAC6 levels and patient outcome. Together, these results indicate that overexpression of Class I HDAC, particularly HDAC1, is associated with poor prognosis in MM.