Genetic and Signaling Abnormalities in Waldenstrom’s Macroglobulinemia

Abstract

The genomic alterations that drive the signaling of Waldenström's macroglobulinemia distinguish it from related malignancies such as marginal zone lymphoma, chronic lymphocytic leukemia, and IgM secreting multiple myeloma. The most frequent of these somatic changes are heterozygous activating MYD88 mutations observed in over 90{\thinspace}{\%} of WM patients and 50--80{\thinspace}{\%} of patients with IgM monoclonal gammopathy of undetermined significance. In addition to MYD88, activating mutations are also found in the carboxyl terminal tail region of CXCR4 in up to 43{\thinspace}{\%} of WM patients. These mutations are often sub-clonal and almost always occur in the context of MYD88 mutations. Together, these mutations impact overall survival, serum IgM, presence of nodal involvement and bone marrow infiltration at diagnosis. Mutant MYD88 drives critical BTK and HCK signaling and is highly predictive of response to the BTK inhibitor ibrutinib. Additional characteristics of these and other recurrent genomic alterations such as ARID1A and CD79B mutations as well as chromosome 6q deletions are discussed.