title: Role of MYD88 in lymphoplasmacytic lymphoma diagnosis and pathogenesis.
abstract: 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.
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Rossi
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D006801:Humans; D009154:Mutation / Q000235:genetics; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000378:metabolism; D008258:Waldenstrom Macroglobulinemia / Q000175:diagnosis* / Q000209:etiology*
chemical_list: D014408:Biomarkers, Tumor; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors