Cao Xin-Xin, Meng Qi, Cai Hao, He Tian-Hua, Zhang Cong-Li, Su Wei, Sun Jian, Li Yue, Xu Wei, Zhou Dao-Bin, Li Jian
Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China.
Department of Laboratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China.
Ann Hematol. 2017 Jun;96(6):971-976. doi: 10.1007/s00277-017-2968-z. Epub 2017 Mar 9.
A broad spectrum of diseases are associated with IgM monoclonal gammopathy, including Waldenstrom macroglobulinemia (WM), various types of B cell non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), primary amyloidosis (AL), and monoclonal gammopathy of undetermined significance (MGUS); these are called IgM monoclonal gammopathy related diseases (IgM-RD). We investigated MYD88 L265P and WHIM-like CXCR4 mutations in various IgM-RD. Patients with serum immunofixation electrophoresis confirmed IgM monoclonal gammopathy who had enough material for DNA extraction and presented between January 2008 and October 2016 at Peking Union Medical College Hospital were enrolled in this cohort. We performed real-time allele-specific-polymerase chain reaction and Sanger sequencing to explore the presence of MYD88 L265P and WHIM-like CXCR4 mutations. One hundred and twelve patients (64 male and 48 female patients) were included in this retrospective study. The median age at diagnosis was 62 years (range, 30-84 years). In total, 64 patients (57.1%) carried the MYD88 L265P mutation and 14 patients (12.5%) carried the CXCR4 WHIM-like mutation. We identified the MYD88 L265P somatic variant in cases with WM (39/42), MGUS (8/18), NHL (14/41, including 4/13 diffuse large B cell lymphoma (DLBCL), 1/8 mucosa-associated lymphoid tissue, 3/6 splenic marginal zone lymphoma (SMZL), 1/4 chronic lymphocytic leukemia, 2/3 nodal marginal zone lymphoma (NMZL), 1/2 mantle cell lymphoma, 1 Burkitt lymphoma, and 1 B cell NHL that could not be classified), primary AL (2/2), and IgM-PN (1/1). The mutation was absent in five patients with Cryoglobulinemia, two with primary cold agglutinin disease and one with MM. The CXCR4 WHIM-like mutation was present in 10/42 patients with WM, 3/41 with NHL (1 DLBCL, 1 SMZL, and 1 NMZL), and 1/18 patients with IgM MGUS. Among the patients with NHL, those with the mutated MYD88 L265P genotype were younger and had lower level of IgG and IgA than the patients with the wild-type genotype. Patients with the mutated MYD88 L265P genotype with WM and MZL were compared. More male patients, higher levels of IgM and lower levels of LDH were found in the WM group. There was no significant difference in overall survival between the two groups. We present a study of the prevalence of the MYD88 L265P mutation and CXCR4 WHIM-like mutation in IgM RD. The MYD88 L265P mutation may play a key role in the pathogenesis of IgM monoclonal gammopathies. It would be interesting in the future to use MYD88 mutation status to differentiate among diseases.
多种疾病与IgM单克隆丙种球蛋白病相关，包括华氏巨球蛋白血症（WM）、各种类型的B细胞非霍奇金淋巴瘤（NHL）、多发性骨髓瘤（MM）、原发性淀粉样变性（AL）以及意义未明的单克隆丙种球蛋白病（MGUS）；这些被称为IgM单克隆丙种球蛋白病相关疾病（IgM-RD）。我们研究了各种IgM-RD中的MYD88 L265P和WHIM样CXCR4突变。血清免疫固定电泳确诊为IgM单克隆丙种球蛋白病且有足够DNA提取材料、于2008年1月至2016年10月在北京协和医院就诊的患者被纳入该队列。我们进行了实时等位基因特异性聚合酶链反应和桑格测序，以探究MYD88 L265P和WHIM样CXCR4突变的存在情况。这项回顾性研究纳入了112例患者（64例男性和48例女性患者）。诊断时的中位年龄为62岁（范围为30 - 84岁）。总共64例患者（57.1%）携带MYD88 L265P突变，14例患者（12.5%）携带CXCR4 WHIM样突变。我们在WM（39/42）、MGUS（8/18）、NHL（14/41，包括4/13弥漫性大B细胞淋巴瘤（DLBCL）、1/8黏膜相关淋巴组织淋巴瘤、3/6脾边缘区淋巴瘤（SMZL）、1/4慢性淋巴细胞白血病、2/3结边缘区淋巴瘤（NMZL）、1/2套细胞淋巴瘤、1例伯基特淋巴瘤和1例无法分类的B细胞NHL）、原发性AL（2/2）和IgM-PN（1/1）病例中鉴定出MYD88 L265P体细胞变异。5例冷球蛋白血症患者、2例原发性冷凝集素病患者和1例MM患者未出现该突变。10/42例WM患者、3/41例NHL患者（1例DLBCL、1例SMZL和1例NMZL）以及1/18例IgM MGUS患者存在CXCR4 WHIM样突变。在NHL患者中，MYD88 L265P基因型突变的患者比野生型基因型患者更年轻且IgG和IgA水平更低。对WM和MZL中MYD88 L265P基因型突变的患者进行了比较。WM组男性患者更多，IgM水平更高，LDH水平更低。两组的总生存期无显著差异。我们展示了一项关于IgM RD中MYD88 L265P突变和CXCR4 WHIM样突变患病率的研究。MYD88 L265P突变可能在IgM单克隆丙种球蛋白病发病机制中起关键作用。未来利用MYD88突变状态区分疾病将很有意义。
