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The following websites contain valuable information regarding the research and treatment of Waldenstrom's Macroglobulinemia:

Please visit our main program website: Bing Center for Waldenstrom's Research. This site contains information on the latest treatment recommendations, abstracts, news and events, current and pending clinical trials and participating institutions, basic research, and publications, as well as photos and brief bios of the Bing Center staff.


Also feel free to visit our WM Workshop Website where you will find information about our most recent conference in August, 2014 in London, UK.

WALDENSTROM’S MACROGLOBULINEMIA/LYMPHOPLASMACYTIC LYMPHOMA (Page 2)

Nature of the Clonal Cell

The WM bone marrow B-cell clone shows intraclonal differentiation from small lymphocytes with large focal deposits of surface immunoglobulins, to lymphoplasmacytic cells, to mature plasma cells that contain intracytoplasmic immunoglobulins.24 Clonal B cells are detectable among blood B lymphocytes, and their number increases in patients who fail to respond to therapy or who progress.25 These clonal blood cells present the peculiar capacity to differentiate spontaneously, in in vitro culture, to plasma cells. This is through an interleukin-6 (IL-6)-dependent process in IgM MGUS and mostly an IL-6-independent process in WM patients.26 All these cells express the monoclonal IgM present in the blood and a variable percentage of them also express surface IgD. The characteristic immunophenotypic profile of the lymphoplasmacytic cells in WM includes the expression of the pan B-cell markers CD19, CD20, CD22, CD79, and FMC7.2. 27–29 Expression of CD5, CD10 and CD23 may be found in 10–20% of cases, and does not exclude the diagnosis of WM.30

The phenotype of lymphoplasmacytic cells in WM cell suggests that the clone is a post-germinal center B-cell. This indication is further strengthened by the results of the analysis of the nature (silent or amino-acid replacing) and distribution (in framework or CDR regions) of somatic mutations in Ig heavy- and light-chain variable regions performed in patients with WM.31,32 This analysis showed a high rate of replacement mutations, compared with the closest germline genes, clustering in the CDR regions and without intraclonal variation. Subsequent studies showed a strong preferential usage of VH3/JH4 gene families, no intraclonal variation, no evidence for any isotype-switched transcripts.33,34 These data indicate that WM may originate from a IgM+ and/or IgM+ IgD+ memory B cell. Normal IgM+ memory B cells localize in bone marrow, where they mature to IgM-secreting cells.35

Bone Marrow Microenvironment

Increased numbers of mast cells are found in the bone marrow of WM patients, wherein they are usually admixed with tumor aggregates.29,36 Recent studies have helped clarify the role of mast cells in WM. Co-culture of primary autologous or mast cell lines with WM LPC resulted in dose-dependent WM cell proliferation and/or tumor colony, primarily through CD40 ligand (CD40L) signaling. Furthermore, WM cells through elaboration of soluble CD27 (sCD27), induced the upregulation of CD40L on mast cells derived from WM patients and mast cell lines37.

Clinical Features

The clinical and laboratory findings at time of diagnosis of WM in one large institutional study7 are presented in Table 1. Unlike most indolent lymphomas, splenomegaly and lymphadenopathy are prominent in only a minority of patients (<15%). Purpura is frequently associated with cryoglobulinemia and more rarely with AL amyloidosis, while hemorrhagic manifestations and neuropathies are multifactorial (see later). The morbidity associated with WM is caused by the concurrence of two main components: tissue infiltration by neoplastic cells and, more importantly, the physicochemical and immunological properties of the monoclonal IgM. As shown in Table 2, the monoclonal IgM can produce clinical manifestations through several different mechanisms related to its physicochemical properties, non-specific interactions with other proteins, antibody activity, and tendency to deposit in tissues.38–40

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