Waldenstrom's Macroglobulinemia

华氏大球蛋白血症（WM）是一种相对罕见的生发后中心淋巴浆细胞性肿瘤，分泌大量IgM。虽然WM与淋巴浆细胞性淋巴瘤和多发性骨髓瘤有一些相似之处，但对WM的分子发病机制知之甚少。我们开展了以下研究：首先，我们获得了唯一推测的WM细胞系（WSU-WM），并对其进行了分子核型分析；失调c-myc的t（8;14）易位的分子特征测定表达mu和c-myc的突变；并对该细胞系表达的基因进行淋巴芯片微阵列分析。不幸的是，一直无法获得原发肿瘤样本来证明该细胞系来源于WM肿瘤，因此该细胞系的结果可能与WM肿瘤无关。其次，我们已经开发了纯化和表征WM肿瘤细胞的技术，主要重点是使用FISH检测特定染色体的非整倍性以及涉及IgH和IgL位点的易位。我们的研究结果表明，在WM中，IgH开关重组和IgH易位是罕见的，这与多性淋巴浆细胞形态一起表明，对IgH开关和浆细胞分化的阻断可能有助于该肿瘤的发病。此外，我们与梅奥诊所的R. Fonseca的合作结果显示：WM肿瘤通常为二倍体或近二倍体，核型异常很少，IgH易位极为罕见。然而，我们发现在至少50%的WM肿瘤中存在6q22小的间质缺失。这些结果提示WM的分子发病机制更像慢性淋巴细胞白血病（CLL）而不是多发性骨髓瘤（MM）。第三，我们正在开发能够使WM肿瘤细胞永生的策略。最后，我们是DCEG项目的合作者，该项目旨在鉴定来自有两个或两个以上WM或IgM MGUS个体的家庭成员的正常细胞和肿瘤细胞中发生的遗传异常。

Waldenstrom's macroglobulinemia (WM) is a relatively rare post-germinal center lymphoplasmacytic tumor that secretes large amounts of IgM. Although WM has some similarities to lymphoplasmacytic lymphoma and multiple myeloma, very little is known about the molecular pathogenesis of WM. We have initiated the following studies. First, we have obtained the only putative WM cell line (WSU-WM) and have studied it by: molecular karyotypic analyses; molecular characterization of a t(8;14) translocation that dysregulates c-myc; determination of mutations in expressed mu and c-myc; and lymphochip microarray analysis of genes expressed in this line. Unfortunately, it has been impossible to obtain a primary tumor sample to prove that this line is derived from a WM tumor, so that the results on this cell line may not relate to WM tumors. Second, we have developed the technology to purify and characterize WM tumor cells, with a major focus of using FISH to detect aneuploidy of specific chromosomes plus translocations involving IgH and IgL loci. Our results indicate that IgH switch recombination and IgH translocations are rare in WM, which together with the pleotropic lymphoplasmacytic morphology suggest that a block to IgH switching and plasma cell differentiation may contribute to the pathogenesis of this tumor. In addition, our collaborative results with R. Fonseca at the Mayo Clinic show the following: WM tumors usually are diploid or near diploid with few karyotypic abnomalities, and IgH translocations are extremely rare. However, we have found that small interstitial deletions at 6q22 are present in at least 50% of WM tumors. These results suggest that the molecular pathogeneis of WM is more like chronic lymphocytic leukemia (CLL) than multiple myeloma (MM). Third, we are developing strategies that may enable us to immortalize WM tumor cells. Finally, we are collaborators in a DCEG project to identify genetic abnormalities that occur in normal and tumor cells derived from individuals who are are members of families that have two or more individuals with WM or IgM MGUS.