Waldenstr？m macroglobulinemia (WM) is a rare and currently incurable neoplasm of IgM-expressing B-lymphocytes that is characterized by the occurrence of a monoclonal IgM (mIgM) paraprotein in blood serum and the infiltration of the hematopoietic bone marrow with malignant lymphoplasmacytic cells. The symptoms of patients with WM can be attributed to the extent and tissue sites of tumor cell infiltration and the magnitude and immunological specificity of the paraprotein. WM presents fascinating clues on neoplastic B-cell development, including the recent discovery of a specific gain-of-function mutation in the MYD88 adapter protein. This not only provides an intriguing link to new findings that natural effector IgM+IgD+ memory B-cells are dependent on MYD88 signaling, but also supports the hypothesis that WM derives from primitive, innate-like B-cells, such as marginal zone and B1 B-cells. Following a brief review of the clinical aspects and natural history of WM, this review discusses the thorny issue of WM’s cell of origin in greater depth. Also included are emerging, genetically engineered mouse models of human WM that may enhance our understanding of the biologic and genetic underpinnings of the disease and facilitate the design and testing of new approaches to treat and prevent WM more effectively. 1. Clinical Aspects of WM: A Brief Overview 1.1. Definition and Classification The 2008 World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues [1] defines Waldenstr？m macroglobulinemia (WM) as a type of lymphoplasmacytic lymphoma (LPL) that involves the bone marrow and is associated with a monoclonal immunoglobulin (Ig) of the M class in the serum. The monoclonal IgM is usually referred to as IgM paraprotein or “M spike”—or mIgM for short. LPL is a low-grade malignancy of the mature B-lymphocyte lineage that exhibits a cytological spectrum of lymphoplasmacytic differentiation that ranges from small B cells to fully differentiated plasma cells (PCs). Between these extremes lies a sizable, if not predominant, fraction of cells with intermediate features and, therefore, designated lymphoplasmacytoid or lymphoplasmacytic cells (LPCs) [2]. Sometimes these cells are referred to as plasmacytoid or plasmacytic lymphocytes. Although LPL is characteristically associated with an mIgM that can be readily detected by serum protein electrophoresis, LPL does not always lead to WM. This is because approximately 5% of LPLs either produce a paraprotein that is not of the M class (but instead belongs in most cases to the A class or
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