2012年09月01日 訊 /生物谷BIOON/ --根據(jù)2012年8月30日刊登在New England Journal of Medicine期刊上的一項(xiàng)研究,，在患有瓦爾登斯特倫巨球蛋白血癥(Waldenström's macroglobulinemia)的病人體內(nèi)，MYD88 L265P是一種常見性的反復(fù)出現(xiàn)的突變,。
來(lái)自美國(guó)波士頓市達(dá)納- 法伯癌癥研究所(Dana Farber Cancer Institute)的Steven P. Treon博士與同事們對(duì)30名瓦爾登斯特倫巨球蛋白血癥病人的骨髓淋巴漿細(xì)胞淋巴癌(lymphoplasmacytic lymphoma, LPL)細(xì)胞進(jìn)行全基因組測(cè)序,。他們還在一項(xiàng)擴(kuò)大的LPL病人群體、患有其他的與LPL擁有一些相同特征的B細(xì)胞疾病的病人和健康供者中使用Sanger測(cè)序法來(lái)驗(yàn)證這項(xiàng)研究發(fā)現(xiàn),。
研究人員在瓦爾登斯特倫巨球蛋白血癥病人體內(nèi)LPL細(xì)胞中的染色體3p22.2位點(diǎn)38182641上鑒定出體細(xì)胞突變(T→C),。他們?cè)趤?lái)自組織樣品經(jīng)過(guò)配對(duì)的10名病人的所有樣品中和來(lái)自組織樣品未經(jīng)配對(duì)的20個(gè)樣品中的17個(gè)當(dāng)中，觀察到這種突變,。這種突變預(yù)示著蛋白MYD88發(fā)生一個(gè)氨基酸改變(L265P),，其中MYD88導(dǎo)致IRAK調(diào)控的NF-κB信號(hào)轉(zhuǎn)導(dǎo)。他們利用Sanger測(cè)序法在54名瓦爾登斯特倫巨球蛋白血癥病人當(dāng)中49個(gè)人和全部3名患有不分泌IgM的LPL的病人中鑒定出MYD88 L265P的存在,。在來(lái)自患有瓦爾登斯特倫巨球蛋白血癥或不分泌IgM的LPL的病人的經(jīng)過(guò)配對(duì)的正常組織樣品和健康供者B細(xì)胞中,，MYD88 L265P是缺失的。
研究人員作出結(jié)論,，“MYD88 L265P是一種常見性的反復(fù)出現(xiàn)的突變,，能夠被用來(lái)區(qū)別B細(xì)胞疾病中具有一些相同特征的瓦爾登斯特倫巨球蛋白血癥和不分泌IgM的LPL。”(生物谷Bioon.com)
doi: 10.1056/NEJMoa1200710
PMC:
PMID:
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.)
