MYD88 L265P in Waldenstrom macroglobulinemia, immunoglobulin M monoclonal gammopathy, and other B-cell lymphoproliferative disorders using conventional and quantitative allele-specific polymerase chain reaction
MYD88 L265P in Waldenstrom macroglobulinemia, immunoglobulin M monoclonal gammopathy, and other B-cell lymphoproliferative disorders using conventional and quantitative allele-specific polymerase chain reaction
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DOI：
10.1182/blood-2012-09-454355
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发表时间：
2013-03-14
期刊：
影响因子：
20.3
通讯作者：
Treon, Steven P.
中科院分区：
文献类型：
--
作者：
Xu, Lian;Hunter, Zachary R.;Treon, Steven P.
通过全基因组和/或Sanger测序，我们最近发现了一种体细胞突变(MYD88 L265P)，它可以刺激核因子kappa B的活性，并且存在于90%的Waldenstrom巨球蛋白血症(WM)患者中。90%的免疫球蛋白M(IgM)单克隆性丙种球病(MGUS)患者中MyD88 L265P缺失。因此，我们开发了常规和实时等位基因特异性聚合酶链式反应(AS-PCR)分析方法，以更灵敏地检测和定量MYD88 L265P。MYD88 L265P在104例WM患者中检出97例(93%)，在24例IgM MGUS患者中检出13例(54%)，在脾边缘带淋巴瘤(2/20；10%)、CLL(1/26；4%)、多发性骨髓瘤(包括IgM患者，0/14)、免疫球蛋白G MGUS(0/9)患者以及健康献血者(0/40；P<；与其他队列相比，WM患者为1.5×10(-5))中检测到MYD88 L265P。实时荧光定量AS-PCR检测显示MYD88 L265P Delta C-T与西医患者骨髓病变的符合率较高(r=0.89，P=0.008)。这些研究发现MYD88 L265P是一种广泛存在于WM和IgM MGUS患者中的突变，使用高度敏感和特异的AS-PCR分析，可能用于诊断、鉴别和/或反应评估。在许多IgM MGUS患者中发现该突变，提示MYD88 L265P可能是WM发病机制中的早期致癌事件。
By whole-genome and/or Sanger sequencing, we recently identified a somatic mutation (MYD88 L265P) that stimulates nuclear factor kappa B activity and is present in >90% of Waldenstrom macroglobulinemia (WM) patients. MYD88 L265P was absent in 90% of immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (MGUS) patients. We therefore developed conventional and real-time allele-specific polymerase chain reaction (AS-PCR) assays for more sensitive detection and quantification of MYD88 L265P. Using either assay, MYD88 L265P was detected in 97 of 104 (93%) WM and 13 of 24 (54%) IgM MGUS patients and was either absent or rarely expressed in samples from splenic marginal zone lymphoma (2/20; 10%), CLL (1/26; 4%), multiple myeloma (including IgM cases, 0/14), and immunoglobulin G MGUS (0/9) patients as well as healthy donors (0/40; P < 1.5 x 10(-5) for WM vs other cohorts). Real-time AS-PCR identified IgM MGUS patients progressing to WM and showed a high rate of concordance between MYD88 L265P Delta C-T and BM disease involvement (r = 0.89, P = .008) in WM patients undergoing treatment. These studies identify MYD88 L265P as a widely present mutation in WM and IgM MGUS patients using highly sensitive and specific AS-PCR assays with potential use in diagnostic discrimination and/or response assessment. The finding of this mutation in many IgM MGUS patients suggests that MYD88 L265P may be an early oncogenic event in WM pathogenesis.