Abstract
A broad spectrum of diseases are associated with IgM monoclonal gammopathy, including Waldenstrom macroglobulinemia (WM), various types of B cell non-Hodgkin’s lymphoma (NHL), multiple myeloma (MM), primary amyloidosis (AL), and monoclonal gammopathy of undetermined significance (MGUS); these are called IgM monoclonal gammopathy related diseases (IgM-RD). We investigated MYD88 L265P and WHIM-like CXCR4 mutations in various IgM-RD. Patients with serum immunofixation electrophoresis confirmed IgM monoclonal gammopathy who had enough material for DNA extraction and presented between January 2008 and October 2016 at Peking Union Medical College Hospital were enrolled in this cohort. We performed real-time allele-specific-polymerase chain reaction and Sanger sequencing to explore the presence of MYD88 L265P and WHIM-like CXCR4 mutations. One hundred and twelve patients (64 male and 48 female patients) were included in this retrospective study. The median age at diagnosis was 62 years (range, 30–84 years). In total, 64 patients (57.1%) carried the MYD88 L265P mutation and 14 patients (12.5%) carried the CXCR4 WHIM-like mutation. We identified the MYD88 L265P somatic variant in cases with WM (39/42), MGUS (8/18), NHL (14/41, including 4/13 diffuse large B cell lymphoma (DLBCL), 1/8 mucosa-associated lymphoid tissue, 3/6 splenic marginal zone lymphoma (SMZL), 1/4 chronic lymphocytic leukemia, 2/3 nodal marginal zone lymphoma (NMZL), 1/2 mantle cell lymphoma, 1 Burkitt lymphoma, and 1 B cell NHL that could not be classified), primary AL (2/2), and IgM-PN (1/1). The mutation was absent in five patients with Cryoglobulinemia, two with primary cold agglutinin disease and one with MM. The CXCR4 WHIM-like mutation was present in 10/42 patients with WM, 3/41 with NHL (1 DLBCL, 1 SMZL, and 1 NMZL), and 1/18 patients with IgM MGUS. Among the patients with NHL, those with the mutated MYD88 L265P genotype were younger and had lower level of IgG and IgA than the patients with the wild-type genotype. Patients with the mutated MYD88 L265P genotype with WM and MZL were compared. More male patients, higher levels of IgM and lower levels of LDH were found in the WM group. There was no significant difference in overall survival between the two groups. We present a study of the prevalence of the MYD88 L265P mutation and CXCR4 WHIM-like mutation in IgM RD. The MYD88 L265P mutation may play a key role in the pathogenesis of IgM monoclonal gammopathies. It would be interesting in the future to use MYD88 mutation status to differentiate among diseases.
Similar content being viewed by others
References
Cao XX, Meng Q, Mao YY et al (2016) The clinical spectrum of IgM monoclonal gammopathy: a single center retrospective study of 377 patients. Leuk Res 46:85–88
Treon SP, Xu L, Yang G et al (2012) MYD88 L265P somatic mutation in Waldenström's macroglobulinemia. N Engl J Med 367:826–833
Xu L, Hunter ZR, Yang G et al (2013) MYD88 L265P in Waldenstro ̈m macroglobulinemia, immunoglobulin M monoclonal gammopathy, and other B-cell lymphoproliferative disorders using conventional and quantitative allele-specific polymerase chain reaction. Blood 121:2051–2058
Treon SP, Cao Y, Xu L et al (2014) Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenström macroglobulinemia. Blood 123:2791–2796
Owen RG, Treon SP, Al-Katib A et al (2003) Clinicopathological definition of Waldenstrom’s macroglobulinemia: consensus panel recommendations from the second international workshop on Waldenstrom’s macroglobulinemia. Semin Oncol 30:110–115
Swerdlow SH, Campo E, Harris NL et al (2008) WHO classification of Tumours of Haematopoitetic and lymphoid tissues. IARC PRESS, Lyon
Palumbo A, Avet-Loiseau H, Oliva S et al (2015) Revised international staging system for multiple myeloma: a report from international myeloma working group. J Clin Oncol 33:2863–2869
Berentsen S, Tjønnfjord GE (2012) Diagnosis and treatment of cold agglutinin mediated autoimmune hemolytic anemia. Blood Rev 26:107–115
Manuel RC, John HS, Maria CC, Bosch X (2012) The cryoglobulinaemias. Lancet 379:348–360
Roccaro AM, Sacco A, Jimenez C et al (2014) C1013G/CXCR4 acts as a driver mutation of tumor progression and modulator of drug resistance in lymphoplasmacytic lymphoma. Blood 123:4120–4131
Varettoni M, Zibellini S, Arcaini L et al (2013a) MYD88 (L265P) mutation is an independent risk factor for progression in patients with IgM monoclonal gammopathy of undetermined significance. Blood 122:2284–2285
Staiger AM, Ott MM, Parmentier S et al (2015) Allele-specific PCR is a powerful tool for the detection of the MYD88 L265P mutation in diffuse large B cell lymphoma and decalcified bone marrow samples. Br J Haematol 171:145–148
Liu F, Karube K, Kato H et al (2012) Mutation analysis of NF-kappa B signal pathway-related genes in ocular MALT lymphoma. Int J Clin Exp Pathol 5:436–441
Yan Q, Huang Y, Watkins AJ et al (2012) BCR and TLR signaling pathways are recurrently targeted by genetic changes in splenic marginal zone lymphomas. Haematologica 97:595–598
Puente XS, Pinyol M, Quesada V et al (2011) Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature 475:101–105
Chakraborty R, Novak AJ, Ansell SM et al (2016) First report of MYD88L265P somatic mutation in IgM-associated light chain amyloidosis. Blood 127:2936–2938
Randen U, Troen G, Tierens A et al (2014) Primary cold agglutinin-associated lymphoproliferative disease: a B-cell lymphoma of the bone marrow distinct from lymphoplasmacytic lymphoma. Haematologica 99:497–504
Varettoni M, Arcaini L, Zibellini S et al (2013b) Prevalence and clinical significance of the MYD88 (L265P) somatic mutation in Waldenstrom’s macroglobulinemia and related lymphoid neoplasms. Blood 121:2522–2528
Martinez-Lopez A, Curiel-Olmo S, Mollejo M et al (2015) MYD88 (L265P) somatic mutation in marginal zone B-cell lymphoma. Am J Surg Pathol 39:644–651
Manasanch EE, Braylan R, Stetler-Stevenson M et al (2014) Lack of MYD88 L265P in non-immunoglobulin M lymphoplasmacytic lymphoma. Leuk Lymphoma 55:1402–1403
Lin P, Hao S, Handy BC et al (2005) Lymphoid neoplasm associated with IgM paraprotein. A study of 382 patients. Am J Clin Pathol 123:200–205
Hunter ZR, Xu L, Yang G et al (2014) The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis. Blood 123:1637–1646
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Xin-xin Cao and Qi Meng have contributed equally to this work.
Rights and permissions
About this article
Cite this article
Cao, Xx., Meng, Q., Cai, H. et al. Detection of MYD88 L265P and WHIM-like CXCR4 mutation in patients with IgM monoclonal gammopathy related disease. Ann Hematol 96, 971–976 (2017). https://doi.org/10.1007/s00277-017-2968-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00277-017-2968-z