NEJM：MYD88 L265P为瓦尔登斯特伦巨球蛋白血症中常见性突变

根据2012年8月30日刊登在New England Journal of Medicine期刊上的一项研究，在患有瓦尔登斯特伦巨球蛋白血症(Waldenström's macroglobulinemia)的病人体内，MYD88 L265P是一种常见性的反复出现的突变。

来自美国波士顿市达纳- 法伯癌症研究所(Dana Farber Cancer Institute)的Steven P. Treon博士与同事们对30名瓦尔登斯特伦巨球蛋白血症病人的骨髓淋巴浆细胞淋巴癌(lymphoplasmacytic lymphoma, LPL)细胞进行全基因组测序。他们还在一项扩大的LPL病人群体、患有其他的与LPL拥有一些相同特征的B细胞疾病的病人和健康供者中使用Sanger测序法来验证这项研究发现。

研究人员在瓦尔登斯特伦巨球蛋白血症病人体内LPL细胞中的染色体3p22.2位点38182641上鉴定出体细胞突变(T→C)。他们在来自组织样品经过配对的10名病人的所有样品中和来自组织样品未经配对的20个样品中的17个当中，观察到这种突变。这种突变预示着蛋白MYD88发生一个氨基酸改变(L265P)，其中MYD88导致IRAK调控的NF-κB信号转导。他们利用Sanger测序法在54名瓦尔登斯特伦巨球蛋白血症病人当中49个人和全部3名患有不分泌IgM的LPL的病人中鉴定出MYD88 L265P的存在。在来自患有瓦尔登斯特伦巨球蛋白血症或不分泌IgM的LPL的病人的经过配对的正常组织样品和健康供者B细胞中，MYD88 L265P是缺失的。

研究人员作出结论，“MYD88 L265P是一种常见性的反复出现的突变，能够被用来区别B细胞疾病中具有一些相同特征的瓦尔登斯特伦巨球蛋白血症和不分泌IgM的LPL。”

doi: 10.1056/NEJMoa1200710
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MYD88 L265P Somatic Mutation in Waldenström's Macroglobulinemia

Steven P. Treon, M.D., Ph.D., Lian Xu, M.S., Guang Yang, Ph.D., Yangsheng Zhou, M.D., Ph.D., Xia Liu, M.D., Yang Cao, M.D., Patricia Sheehy, N.P., Robert J. Manning, B.S., Christopher J. Patterson, M.A., Christina Tripsas, M.A., Luca Arcaini, M.D., Geraldine S. Pinkus, M.D., Scott J. Rodig, M.D., Ph.D., Aliyah R. Sohani, M.D., Nancy Lee Harris, M.D., Jason M. Laramie, Ph.D., Donald A. Skifter, Ph.D., Stephen E. Lincoln, Ph.D., and Zachary R. Hunter, M.A.

Background
Waldenström's macroglobulinemia is an incurable, IgM-secreting lymphoplasmacytic lymphoma (LPL). The underlying mutation in this disorder has not been delineated.
Methods
We performed whole-genome sequencing of bone marrow LPL cells in 30 patients with Waldenström's macroglobulinemia, with paired normal-tissue and tumor-tissue sequencing in 10 patients. Sanger sequencing was used to validate the findings in samples from an expanded cohort of patients with LPL, those with other B-cell disorders that have some of the same features as LPL, and healthy donors.
Results
Among the patients with Waldenström's macroglobulinemia, a somatic variant (T→C) in LPL cells was identified at position 38182641 at 3p22.2 in the samples from all 10 patients with paired tissue samples and in 17 of 20 samples from patients with unpaired samples. This variant predicted an amino acid change (L265P) in MYD88, a mutation that triggers IRAK-mediated NF-κB signaling. Sanger sequencing identified MYD88 L265P in tumor samples from 49 of 54 patients with Waldenström's macroglobulinemia and in 3 of 3 patients with non–IgM-secreting LPL (91% of all patients with LPL). MYD88 L265P was absent in paired normal tissue samples from patients with Waldenström's macroglobulinemia or non-IgM LPL and in B cells from healthy donors and was absent or rarely expressed in samples from patients with multiple myeloma, marginal-zone lymphoma, or IgM monoclonal gammopathy of unknown significance. Inhibition of MYD88 signaling reduced IκBα and NF-κB p65 phosphorylation, as well as NF-κB nuclear staining, in Waldenström's macroglobulinemia cells expressing MYD88 L265P. Somatic variants in ARID1A in 5 of 30 patients (17%), leading to a premature stop or frameshift, were also identified and were associated with an increased disease burden. In addition, 2 of 3 patients with Waldenström's macroglobulinemia who had wild-type MYD88 had somatic variants in MLL2.
Conclusions
MYD88 L265P is a commonly recurring mutation in patients with Waldenström's macroglobulinemia that can be useful in differentiating Waldenström's macroglobulinemia and non-IgM LPL from B-cell disorders that have some of the same features. (Funded by the Peter and Helen Bing Foundation and others.)