Lymphoplasmacytic lymphoma (LPL) is a distinct B-cell lymphoproliferative disorder primarily characterized by bone marrow infiltration of lymphoplasmacytic cells. When LPL produces a serum monoclonal immunoglobulin of the IgM class, it is termed Waldenström macroglobulinemia (WM). The differential diagnosis between LPL and other types of morphologically similar B-cell tumors that may also have plasmacytic differentiation and/or secretion of IgM paraproteins is not always clear-cut based solely on the pathologic and phenotypic features of the tumor. Although the current treatments for LPL/WM are initially effective in inducing responses in most patients, they are not curative and show decreasing efficacy with repeated administrations, ultimately resulting in the selection of a chemoresistant clone. Next-generation sequencing studies have identified somatic mutations of MYD88, a key component of the Toll-like receptor signaling machinery, in ∼90% of LPL/WM. Deregulated MYD88 signaling promoted by mutations sustains tumor cell survival in LPL/WM, demonstrating that they are gain-of-function driver events in this lymphoma. This review discusses the molecular and biological mechanisms underlying MYD88 mutations in LPL/WM, the role of MYD88 mutations as molecular biomarker for the refinement of diagnosis and the improvement classification of LPL/WM, and novel targeted therapeutic strategies for LPL/WM based on the pharmacological manipulation of MYD88 signaling to which this lymphoma is addicted.
© 2014 by The American Society of Hematology. All rights reserved.