MCD88 ^L265P And CXCR4 ^WHIM Gene Mutations In IgM-related Diseases Of Myoglobin And Other Monoclonal IgM-related Diseases

Background and Objectives:Waldenstrom macroglobulinemia (WM) is a lymphoplasmacytic lymphoma characterized by serum monoclonal IgM immunoglobulin. The presence of IgM monoclonal gammopathy can occur in a broad spectrum of diseases, including WM, various B cell non-Hodgkin’s lymphoma (NHL), monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), primary amyloidosis (AL), and so on. Immunofixation electrophoresis shows IgM K/A positive in this series of diseases. Recently, the high mutation rates of MYD88L265P and CXCR4WHIM mutation had been documented in WM. We investigated the presence of MYD88L265P and CXCR4WHIM mutation in WM and other IgM monoclonal gammopathy related diseases.Methods:We analyzed retrospectively the clinical data of 90 symptomatic WM patients first diagnosed in Peking Union Medical College hospital from Janunary,2000 to April, 2016.49 fresh samples and 15 formalin-fixed, paraffin-embedded (FFPE) tissues of WM from different sources were detected by both Real-time AS-PCR and AS-PCR for MYD88L265P. We performd Real-time AS-PCR, AS-PCR and Sanger sequencing in 93 patients of IgM monoclonal gammopathy related diseases to explore the presence of MYD88L265P and CXCR4WHIM mutation. MYD88L265P in cerebrospinal fluid (CSF) of 2 patients diagnosed with Bing-Neel syndrome (BNS) were monitored.Results:90 symptomatic WM patients were included. The median age is 64.5 years old. The most common symptoms are anemia, B symptomos, lymphadenopathy, splenohepatomegalia, hyperviscosity, skin and mucosal bleeding. Several patients had secondary amyloidosis, peripheral neuropathy, cryoglobulinaemia and BNS. According to the International Prognostic Scoring System for symptomatic WM (WPSS), we included 18 low-risk,41 intermediate-risk and 31 high risk patients. With a median follow-up of 44 months, the median survivals were 80 months in total and 37 months,84 months and not reached for high-risk, intermediate-risk and low-risk patients, respectively.75 patiens were treated and the response could be accessed. 50 patients received new drugs represented by rituximab/bendamustine/ thalidomide, while 25 patients were treated with traditional drugs including fludarabine or alkylating agent. The median survival of the new-drug group was longer than the traditional-drug group.The sensitivities of Real-time AS-PCR and AS-PCR for MYD88L265P are 0.16%and 1%, respectively. Comparing the results of the two methods, we found that for bone marrow CD19+ sorting cells, the detection rates were identical; while in bone marrow aspirates and FFPE tissues, Real-time AS-PCR could function better.In 93 patients of IgM monoclonal gammopathy related diseases, the most common ones were WM, B-NHL and IgM-MGUS; there were several primary cryoglobulinaemia (pCAD), cryoglobulinemia, primary AL, MM and Castleman’s disease (CD). The mutation rates of MYD88L265P in WM, smoldering WM (sWM), IgM-MGUS, diffuse large B cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), marginal zone lymphoma (MZL), mucosa-associated lymphoid tissue (MALT) are 93.8%,40%,44.4%,42.9%,60%, 33.3%,14.3%. CXCR4WHIM mutation were found in 21.9% of WM,20% of sWM,0% in IgM-MGUS and 7.1% in DLBCL. MYD88L265P mutation were positive in the CSF of 2 BNS patients and disappeared with effective therapies.Conclusions:The clinical presentations of WM are diverse. WPSS is valuable in making risk-adapted treatment decisions and has prognostic significance. Patients can benefit from new drugs in the long survival. For the detection of MYD88L265P in bone marrow CD19+ sorting cells, we can use either Real-time AS-PCR or AS-PCR; but Real-time AS-PCR is more functional in bone marrow aspirates and FFPE tisstue. The presence of MYD88L265P and CXCR4WHIM mutation were much higher in WM than other IgM monoclonal gammopathy related diseases. The mutation rates of MYD88L265P were higher in IgM positive DLBCL and CLL/SLL than previously reported. WM patients harboring MYD88L265P CXCR4WHIM were elder at diagnosis, had higher concentration of monoclonal protein and bone marrow disease burden. The mutation status of CXCR4WHIM had no impact on the overall survival. Identification of MYD88L265P mutation might be a new molecular-based biomarker tool to add to the diagnostic and monitoring armamentarium for BNS.