Waldenstrom's Macroglobulinemia

Waldenstrom‘s巨球蛋白血症(WM)是一种相对罕见的生发中心后淋巴浆细胞肿瘤，可分泌大量的IgM。尽管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，我们获得了唯一可能的WM细胞系(WSU-WM)，并对其进行了以下研究：分子核型分析；调节c-myc的t(8；14)易位的分子特征；u和c-myc表达突变的测定；以及对该细胞系中表达的基因的淋巴芯片芯片分析。不幸的是，一直无法获得原发肿瘤样本来证明该细胞系来自于WM肿瘤，因此该细胞系的结果可能与WM肿瘤无关。其次，我们开发了提纯和鉴定WM肿瘤细胞的技术，重点是使用FISH检测特定染色体的非整倍体以及涉及IGH和IGL基因座的易位。我们的结果表明，在WM中，IgH开关重组和IgH易位是罕见的，再加上多形性淋巴浆细胞的形态，提示阻止IGH开关和浆细胞分化可能参与了该肿瘤的发病机制。此外，我们在梅奥诊所与R.Fonseca的合作结果显示：WM肿瘤通常是二倍体或近二倍体，很少有核型异常，IGH易位极其罕见。然而，我们发现在至少50%的WM肿瘤中存在6q22的小间质缺失。提示WM的分子发病机制更像是慢性淋巴细胞白血病(CLL)，而不是多发性骨髓瘤(MM)。第三，我们正在开发可能使WM肿瘤细胞永生的策略。最后，我们是DCEG项目的合作者，该项目旨在识别发生在正常细胞和肿瘤细胞中的基因异常，这些细胞来自有两个或更多患有WM或IgM MGUS的家庭成员。

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.