Natural history of WM. (A) One major gap in our current understanding of WM is that no definitive cause has been identified. Although autoimmune and inflammatory conditions have been shown to increase the risk of WM [107], the fundamental biological mechanism underlying risk elevation by these conditions remains unclear. Early observations on familial clustering of WM have prompted additional studies on hereditary predisposition in affected families, case-control studies, and cohort studies—all with the goal of identifying the underlying “WM genes” or—to use a more appropriate scientific term—the susceptibility alleles of WM [108]. This effort has uncovered allelic variants of IL10, TNFSF10, IL6, and BCL2 as candidate WM genes [109]. The latter two are of particular interest because an increase in BCL2 expression has been implicated in enhanced B-lymphocyte survival and hypergammaglobulinemia in familial WM [110], and IL-6 is upregulated in LPL-WM cells [111]. (B) The traditional view postulates that WM is derived from an antigen-experienced, post-GC “memory-like” B lymphocyte, but more recent insights into IgM memory have raised doubt whether GC passage is a requirement for generating WM precursors. Like normal IgM⁺ memory B cells, which can mature to IgM-secreting plasma cells in the bone marrow [112], WM cells differentiate into lymphoplasmacytic cells and plasma cells in the bone marrow [113]. Clonally related IgM⁺ B cells are also detected in the peripheral blood of WM patients, and their numbers increase in patients who progress or fail to respond to therapy [114]. In IgM MGUS patients, these cells possess the peculiar capacity to differentiate spontaneously, in an IL-6-dependent manner, into plasma cells [115]. In WM patients, however, this differentiation is largely independent of IL-6 [115]. Elucidating the mechanism responsible for the switch from IL-6 dependence to independence is an outstanding question in WM research. (C) IgM MGUS is a premalignant expansion of a single clone of aberrant lymphoplasmacytic cells that often precedes the emergence of frank WM [116]. IgM MGUS confers, on average, a 46-fold elevation of the risk to progress to WM [74]. Evidence for a genetic predisposition to MGUS is currently emerging [115, 117, 118]. Identification of the genes or pathways that drive the transition from precursor B cell to IgM MGUS and the subsequent progression of IgM MGUS to WM may lead to new interventions in WM. (D) Global gene expression profiling (GEP), array-based comparative genomic hybridization (aCGH), fluorescence in situ hybridization (FISH), and other genomic and cytogenetic methods have advanced our understanding of the changes in the LPL-WM genome [119]. For example, cytogenetic studies uncovered recurrent deletions of chromosome 6q, an adverse prognosticator for WM patients, presumably due to the loss of an important yet unidentified WM suppressor gene [120]. GEP first suggested that WM is very similar to CLL [111]; however, as pointed out in a commentary [116], further analysis of bone marrow cells that were first fractionated into CD19⁺ and CD138⁺ subpopulations by fluorescence-activated cell sorting (FACS) [103] revealed that this similarity is only superficial. Array CGH revealed that deletion of TRAF3 (a possible cause of NFκB activation in WM) and a loss of miR15/16 (two microRNAs) are involved in BCL-2 upregulation in tumor cells [121]. MicroRNA profiling [122, 123], antibody-based protein arrays [124], and other emerging methods will no doubt reveal additional changes in the WM genome. In analogy to many other types of cancer, the new results will likely lead to the identification of genetic subgroups of LPL-WM and to patient stratification based thereon.