A novel MYD88 mutation, L265RPP, in Waldenström macroglobulinemia activates the NF-κB pathway to upregulate Bcl-xL expression and enhances cell survival

Waldenström macroglobulinemia (WM) is a distinct clinicopathological entity defined by a low-grade B-cell lymphoma, lymphoplasmacytic lymphoma, infiltrating the bone marrow and producing a monoclonal immunoglobulin of the IgM class. 1 Recently, a distinct mutation in MYD88, L265P, has been found in more than 90% of patients with WM. 2 On the other hand, various MYD88 mutations have been found in about 40% of cases with activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL), with MYD88 L265P constituting 75–80% of these mutations. 3 However, MYD88 L265P represents almost the sole MYD88 mutation reported so far in WM and in 50–60% of patients with the IgM-type monoclonal gammopathy of undetermined significance, which may precede WM. 1 , 2 , 4 This mutation has been found in <10% of patients with other low-grade B-cell neoplasms showing plasmacytic differentiation and producing a monoclonal IgM protein, such as splenic marginal zone lymphoma, chronic lymphocytic leukemia and IgM-secreting multiple myeloma. Thus, detection of this mutation is valuable for the differential diagnosis of WM from these low-grade B-cell neoplasms, leading to the development of highly sensitive allele-specific PCR (AS-PCR) methods to detect specifically the MYD88 L265P mutation. 1 , 5 , 6 , 7 , 8