Waldenstrom's Macroglobulinemia


Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Paraproteinemias
  • Genetic Predisposition
  • Trisomy
  • Immunoglobulin Heavy Chains
  • DNA Sequence Analysis
  • Translocation
  • Amino Acid Substitution
  • Chromosome 6
  • IL4
  • Pedigree
  • Genes, Immunoglobulin
  • Molecular Sequence Data
  • Multiple Myeloma
  • Case-Control Studies
  • Chromosome Aberrations
  • CXCR4
  • Chromosome Deletion
  • Polymerase Chain Reaction
  • Flow Cytometry
  • Mutation
  • Chromosome Disorders
  • DNA Mutational Analysis
  • Bone Marrow
  • Signal Transduction
  • Disease Progression
  • Base Sequence
  • IL6
  • Gene Expression Profiling
  • Monoclonal Gammopathy of Undetermined Significance
  • Immunophenotyping
  • Immunoglobulin M
  • Waldenstrom's Macroglobulinemia
  • Immunoglobulin G
  • FISH
  • MYD88
  • Karyotyping
  • MicroRNAs
  • Gene Rearrangement, B-Lymphocyte, Heavy Chain
  • B-Lymphocytes
  • Chronic Lymphocytic Leukemia
Tag cloud generated 10 March, 2017 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (15)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

MYD88 3p22 MYD88D -MYD88 and Waldenstrom's Macroglobulinemia
IGH 14q32.33 IGD1, IGH@, IGHJ, IGHV, IGHD@, IGHJ@, IGHV@, IGH.1@, IGHDY1 -IGH and Waldenstrom's Macroglobulinemia
CXCR4 2q21 FB22, HM89, LAP3, LCR1, NPYR, WHIM, CD184, LAP-3, LESTR, NPY3R, NPYRL, WHIMS, HSY3RR, NPYY3R, D2S201E -CXCR4 and Waldenstrom's Macroglobulinemia
HAS1 19q13.4 HAS -HAS1 and Waldenstrom's Macroglobulinemia
IL6 7p21 HGF, HSF, BSF2, IL-6, IFNB2 -IL6 and Waldenstrom's Macroglobulinemia
IRAK2 3p25.3 IRAK-2 -IRAK2 and Waldenstrom's Macroglobulinemia
IRAK1 Xq28 IRAK, pelle -IRAK1 and Waldenstrom's Macroglobulinemia
HDAC4 2q37.3 HD4, AHO3, BDMR, HDACA, HA6116, HDAC-4, HDAC-A -HDAC4 and Waldenstrom's Macroglobulinemia
FCGR2B 1q23 CD32, FCG2, CD32B, FCGR2, IGFR2 -FCGR2B and Waldenstrom's Macroglobulinemia
EGLN1 1q42.1 HPH2, PHD2, SM20, ECYT3, HALAH, HPH-2, HIFPH2, ZMYND6, C1orf12, HIF-PH2 -EGLN1 and Waldenstrom's Macroglobulinemia
GZMB 14q11.2 HLP, CCPI, CGL1, CSPB, SECT, CGL-1, CSP-B, CTLA1, CTSGL1 -GZMB and Waldenstrom's Macroglobulinemia
EGLN3 14q13.1 PHD3, HIFPH3, HIFP4H3 -EGLN3 and Waldenstrom's Macroglobulinemia
IL4 5q31.1 BSF1, IL-4, BCGF1, BSF-1, BCGF-1 -IL4 and Waldenstrom's Macroglobulinemia
CRP 1q23.2 PTX1 -CRP and Waldenstrom's Macroglobulinemia
PTPRC 1q31-q32 LCA, LY5, B220, CD45, L-CA, T200, CD45R, GP180 -PTPRC and Waldenstrom's Macroglobulinemia

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications

King RL, Gonsalves WI, Ansell SM, et al.
Lymphoplasmacytic Lymphoma With a Non-IgM Paraprotein Shows Clinical and Pathologic Heterogeneity and May Harbor MYD88 L265P Mutations.
Am J Clin Pathol. 2016; 145(6):843-51 [PubMed] Related Publications
OBJECTIVES: Lymphoplasmacytic lymphoma (LPL) with non-immunoglobulin M (IgM) paraproteinemia remains poorly understood. The goal of this study was to investigate the clinicopathologic features of LPL in the bone marrow in patients with immunoglobulin G (IgG) or immunoglobulin A (IgA) paraproteins and evaluate MYD88 L265P mutation status to determine the relationship of these cases to Waldenström macroglobulinemia (WM).
METHODS: Bone marrows from LPL cases with IgG or IgA paraproteins diagnosed between January 1, 2007, and June 30, 2014, were retrieved from the clinical archive. Clinicopathologic features were retrospectively reviewed. MYD88 L265P mutation status was assessed by allele-specific polymerase chain reaction prospectively on all cases.
RESULTS: Of 27 cases, four were reclassified as multiple myeloma, all MYD88 mutation negative. MYD88 L265P mutations were present in 10 (43%) of 23 remaining cases. No association between MYD88 status and bone marrow morphologic or phenotypic features, including the presence of Dutcher bodies, mast cells, expression of CD19 by plasma cells, or hemosiderin, was identified, although these features were present in a subset of cases, similar to WM. Clinical features of WM such as hyperviscosity were uncommon in this group and did not correlate with MYD88 status.
CONCLUSIONS: Non-IgM LPLs are a clinically and pathologically heterogeneous group and often harbor MYD88 L265P mutation, albeit at a lower rate than classic WM. MYD88 status does not correlate with any specific pathologic or clinical manifestations.

Kutálková K, Sedlaříková L, Adam Z, Ševčíková S
[Gene mutations connected to Waldenstöm macroglobulinemia].
Vnitr Lek. 2016; 62(1):40-3 [PubMed] Related Publications
Waldenstöm macroglobulinemia (WM) is a rare lymphoproliferative disorder, currently classified as a monoclonal gammopathy, with incidence rate of 3 per million. The disease is characterized by presence of clonal B lymphocytes in the bone marrow and by presence of monoclonal immunoglobulin IgM in serum. It is mostly an indolent disorder, with median overall survival 6 years. Molecular pathogenesis of WM remains unclear, but deletion of 6q and 13q, trisomy of chromosomes 4 and 8 seem to be typical. Mutations of MYD88(L265P) and CXCR4(WHIM) are very common for WM and affect growth and survival of malignant cells. This work is aimed at the current knowledge of chromosomal aberrations and gene mutations connected to the pathophysiology of WM.

Grunenberg A, Buske C
[New developments in Waldenström's macroglobulinemia].
Dtsch Med Wochenschr. 2016; 141(3):170-2 [PubMed] Related Publications
Waldenström's Macroglobulinemia (WM) is a rare subtype of B-cell lymphoma with mostly indolent course. Until now the backbone of therapy is still Rituximab / Chemotherapy. In recent years whole genome sequencing has revealed a number of genetic mutations, among them mutations of the MYD88 gene which occurs in over 90 % of patients and helps to validate diagnosis of WM in difficult cases. With the introduction of ibrutinib, an oral bruton-tyrosine-kinase inhibitor, an effective chemotherapy-free treatment option is available.

Albitar A, Ma W, DeDios I, et al.
Positive selection and high sensitivity test for MYD88 mutations using locked nucleic acid.
Int J Lab Hematol. 2016; 38(2):133-40 [PubMed] Related Publications
INTRODUCTION: Detection of mutations in the myeloid differentiation primary response gene 88 (MYD88) has clinical implications on diagnosis and therapy, especially in patients with Waldenström's macroglobulinemia (WM) and IgM monoclonal gammopathy of unknown significance (IgM-MGUS). We describe a method that provides greatly increased sensitivity for detecting minority mutations in MYD88.
METHODS: We used a locked nucleic acid oligonucleotide to block amplification of wild-type DNA during polymerase chain reaction (PCR). Sanger sequencing of amplified DNA was used for detecting mutations in MYD88 gene. This approach was used to test samples from patients with WM and IgM-MGUS.
RESULTS: When compared to traditional PCR followed by Sanger sequencing, our methodology was significantly more sensitive (one mutant allele in a background of 200 wild-type alleles). Using sequencing allowed us to visualize the PCR product, giving advantages over other methodologies such as allele-specific PCR. Based on analyzing 36 randomly selected, MYD88 mutated, clinically tested samples, we demonstrate that traditional PCR failed to detect MYD88 mutations in 64% of the samples that were clearly positive by wild-type blocking PCR.
CONCLUSION: The new methodology is essential for attaining accurate results in clinical testing.

Xu L, Hunter ZR, Tsakmaklis N, et al.
Clonal architecture of CXCR4 WHIM-like mutations in Waldenström Macroglobulinaemia.
Br J Haematol. 2016; 172(5):735-44 [PubMed] Related Publications
CXCR4(WHIM) somatic mutations are distinctive to Waldenström Macroglobulinaemia (WM), and impact disease presentation and treatment outcome. The clonal architecture of CXCR4(WHIM) mutations remains to be delineated. We developed highly sensitive allele-specific polymerase chain reaction (AS-PCR) assays for detecting the most common CXCR4(WHIM) mutations (CXCR4(S338X C>A and C>G) ) in WM. The AS-PCR assays detected CXCR4(S338X) mutations in WM and IgM monoclonal gammopathy of unknown significance (MGUS) patients not revealed by Sanger sequencing. By combined AS-PCR and Sanger sequencing, CXCR4(WHIM) mutations were identified in 44/102 (43%), 21/62 (34%), 2/12 (17%) and 1/20 (5%) untreated WM, previously treated WM, IgM MGUS and marginal zone lymphoma patients, respectively, but no chronic lymphocytic leukaemia, multiple myeloma, non-IgM MGUS patients or healthy donors. Cancer cell fraction analysis in WM and IgM MGUS patients showed CXCR4(S338X) mutations were primarily subclonal, with highly variable clonal distribution (median 35·1%, range 1·2-97·5%). Combined AS-PCR and Sanger sequencing revealed multiple CXCR4(WHIM) mutations in many individual WM patients, including homozygous and compound heterozygous mutations validated by deep RNA sequencing. The findings show that CXCR4(WHIM) mutations are more common in WM than previously revealed, and are primarily subclonal, supporting their acquisition after MYD88(L265P) in WM oncogenesis. The presence of multiple CXCR4(WHIM) mutations within individual WM patients may be indicative of targeted CXCR4 genomic instability.

Poulain S, Roumier C, Venet-Caillault A, et al.
Genomic Landscape of CXCR4 Mutations in Waldenström Macroglobulinemia.
Clin Cancer Res. 2016; 22(6):1480-8 [PubMed] Related Publications
PURPOSE: Whole-genome sequencing has revealed MYD88 L265P and CXCR4 mutations (CXCR4(mut)) as the most prevalent somatic mutations in Waldenström macroglobulinemia. CXCR4 mutation has proved to be of critical importance in Waldenström macroglobulinemia, in part due to its role as a mechanism of resistance to several agents. We have therefore sought to unravel the different aspects of CXCR4 mutations in Waldenström macroglobulinemia.
EXPERIMENTAL DESIGN: We have scanned the two coding exons of CXCR4 in Waldenström macroglobulinemia using deep next-generation sequencing and Sanger sequencing in 98 patients with Waldenström macroglobulinemia and correlated with SNP array landscape and mutational spectrum of eight candidate genes involved in TLR, RAS, and BCR pathway in an integrative study.
RESULTS: We found all mutations to be heterozygous, somatic, and located in the C-terminal domain of CXCR4 in 25% of the Waldenström macroglobulinemia. CXCR4 mutations led to a truncated receptor protein associated with a higher expression of CXCR4. CXCR4 mutations pertain to the same clone as to MYD88 L265P mutations but were mutually exclusive to CD79A/CD79B mutations (BCR pathway). We identified a genomic signature in CXCR4(mut) Waldenström macroglobulinemia traducing a more complex genome. CXCR4 mutations were also associated with gain of chromosome 4, gain of Xq, and deletion 6q.
CONCLUSIONS: Our study panned out new CXCR4 mutations in Waldenström macroglobulinemia and identified a specific signature associated to CXCR4(mut), characterized with complex genomic aberrations among MYD88L265P Waldenström macroglobulinemia. Our results suggest the existence of various genomic subgroups in Waldenström macroglobulinemia.

Swerdlow SH, Kuzu I, Dogan A, et al.
The many faces of small B cell lymphomas with plasmacytic differentiation and the contribution of MYD88 testing.
Virchows Arch. 2016; 468(3):259-75 [PubMed] Free Access to Full Article Related Publications
Plasmacytic differentiation may occur in almost all small B cell lymphomas (SBLs), although it varies from being uniformly present (as in lymphoplasmacytic lymphoma (LPL)) to very uncommon (as in mantle cell lymphomas (MCLs)). The discovery of MYD88 L265P mutations in the vast majority of LPLs has had a major impact on the study of these lymphomas. Review of the cases contributed to the 2014 European Association for Haematopathology/Society for Hematopathology slide workshop illustrated how mutational testing has helped refine the diagnostic criteria for LPL, emphasizing the importance of identifying a clonal monotonous lymphoplasmacytic population and highlighting how LPL can still be diagnosed with extensive nodal architectural effacement, very subtle plasmacytic differentiation, follicular colonization, or uncommon phenotypes such as CD5 or CD10 expression. MYD88 L265P mutations were found in 11/11 LPL cases versus only 2 of 28 other SBLs included in its differential diagnosis. Mutational testing also helped to exclude other cases that would have been considered LPL in the past. The workshop also highlighted how plasmacytic differentiation can occur in chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular lymphoma, SOX11 negative MCL, and particularly in marginal zone lymphomas, all of which can cause diagnostic confusion with LPL. The cases also highlighted the difficulty in distinguishing lymphomas with marked plasmacytic differentiation from plasma cell neoplasms. Some SBLs with plasmacytic differentiation can be associated with amyloid, other immunoglobulin deposition, or crystal-storing histiocytosis, which may obscure the underlying neoplasm. Finally, although generally indolent, LPL may transform, with the workshop cases suggesting a role for TP53 abnormalities.

Frank C, Fallah M, Chen T, et al.
Search for familial clustering of multiple myeloma with any cancer.
Leukemia. 2016; 30(3):627-32 [PubMed] Related Publications
Multiple myeloma (MM) is a disease of immunoglobulin-producing plasma cells, which reside mainly in the bone marrow. Family members of MM patients are at a risk of MM, but whether other malignancies are in excess in family members is not established and is the aim of this study. MM patients (24 137) were identified from the Swedish Cancer Registry from years 1958 to 2012. Relative risks (RRs) were calculated for MM defined by any cancer diagnosed in first-degree relatives and compared with individuals whose relatives had no cancer. MM was reliably associated with relative's colorectal, breast and prostate cancers, non-thyroid endocrine tumors, leukemia and cancer of unknown primary; in addition, MM was associated with subsites of bone and connective tissue tumors and of non-Hodgkin lymphoma, including lymphoplasmacytic lymphoma/Waldenström macroglobulinema (RR 3.47). MM showed a strong association (RR 1.91) in colorectal cancer families, possibly as part of an unidentified syndrome. All the associations of MM with discordant cancers are novel suggesting that MM shares genetic susceptibility with many cancers. The associations of MM bone and connective tissue tumors were supported by at least two independent results. Whether the results signal bone-related biology shared by MM and these tumors deserves further study.

Xu X, Yang W, Zhang X
[Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia with P53 deletion and TCR-delta rearrangement in a case].
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2015; 32(5):674-8 [PubMed] Related Publications
OBJECTIVE To study the morphology, immunology, cyto- and molecular genetics of a patient with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM), deletion of P53 gene and rearrangement of clonal T cell receptors-delta (TCR-delta) gene. METHODS The cell morphology and immunocytochemistry were analyzed by bone marrow testing and biopsy. Cellular immunology was analyzed by flow cytometry. Genetic analysis was carried out by chromosome karyotyping, fluorescent in situ hybridization (FISH) and polymerase chain reaction (PCR). Immunoglobulin M (IgM) in serum and urine was assayed by immunofixation electrophoresis. And the effect of chlorambucil therapy was evaluated. RESULTS Bone marrow biopsy suggested that the patient was of B lymphocyte type and had abnormal increase of lymphocytoid plasma cells, which were CD38 and CD138 positive. The patient had a normal male karyotype. FISH and PCR analysis of peripheral blood samples suggested deletion of P53 gene and rearrangement of TCR-delta gene. Immunofixation electrophoresis has detected IgM-kappa in both serum and urine. The patient showed partial response to chlorambucil. CONCLUSION In addition to typical clinical features, bone marrow examination, flow cytometry, histochemistry and immunophenotyping, testing for P53 gene deletion and lymphocyte gene rearrangement can facilitate the diagnosis and treatment of LPL/WM.

Tanaka Y, Kobayashi Y, Maeshima AM, et al.
Intravascular large B-cell lymphoma secondary to lymphoplasmacytic lymphoma: a case report and review of literature with clonality analysis.
Int J Clin Exp Pathol. 2015; 8(3):3339-43 [PubMed] Free Access to Full Article Related Publications
Intravascular large B-cell lymphoma (IVLBCL) can be a fatal malignancy mainly because of difficulty in early detection. Due to the lack of specific clinical manifestations, early detection of IVLBCL remains a challenge, especially in the presence of comorbidities. Lymphoplasmacytic lymphoma (LPL) is an indolent B-cell lymphoma accompanied by monoclonal immunoglobulin M protein in most patients, and known to be associated with high risk of secondary hematological malignancies. Here, we report a patient who developed IVLBCL during treatment for LPL that presented a diagnostic challenge. Rearrangement analysis of the immunoglobulin heavy chain revealed the different clonal origins of two lymphomas, implying a predisposition of LPL to develop unrelated secondary lymphoma. Secondary lymphoma including IVLBCL during the treatment for LPL deserves consideration in order to facilitate early diagnosis and intervention.

Rajkumar SV
Blood. 2015; 125(15):2318-9 [PubMed] Related Publications
In this issue of Blood, Paiva et al provide important information on the cell of origin in Waldenström macroglobulinemia (WM), a longstanding puzzle due to conflicting and incomplete data.

Paulus A, Chitta KS, Wallace PK, et al.
Immunophenotyping of Waldenströms macroglobulinemia cell lines reveals distinct patterns of surface antigen expression: potential biological and therapeutic implications.
PLoS One. 2015; 10(4):e0122338 [PubMed] Free Access to Full Article Related Publications
Waldenströms macroglobulinemia (WM) is a subtype of Non-Hodgkin's lymphoma in which the tumor cell population is markedly heterogeneous, consisting of immunoglobulin-M secreting B-lymphocytes, plasmacytoid lymphocytes and plasma cells. Due to rarity of disease and scarcity of reliable preclinical models, many facets of WM molecular and phenotypic architecture remain incompletely understood. Currently, there are 3 human WM cell lines that are routinely used in experimental studies, namely, BCWM.1, MWCL-1 and RPCI-WM1. During establishment of RPCI-WM1, we observed loss of the CD19 and CD20 antigens, which are typically present on WM cells. Intrigued by this observation and in an effort to better define the immunophenotypic makeup of this cell line, we conducted a more comprehensive analysis for the presence or absence of other cell surface antigens that are present on the RPCI-WM1 model, as well as those on the two other WM cell lines, BCWM.1 and MWCL-1. We examined expression of 65 extracellular and 4 intracellular antigens, comprising B-cell, plasma cell, T-cell, NK-cell, myeloid and hematopoietic stem cell surface markers by flow cytometry analysis. RPCI-WM1 cells demonstrated decreased expression of CD19, CD20, and CD23 with enhanced expression of CD28, CD38 and CD184, antigens that were differentially expressed on BCWM.1 and MWCL-1 cells. Due to increased expression of CD184/CXCR4 and CD38, RPCI-WM1 represents a valuable model in which to study the effects anti-CXCR4 or anti-CD38 targeted therapies that are actively being developed for treatment of hematologic cancers. Overall, differences in surface antigen expression across the 3 cell lines may reflect the tumor clone population predominant in the index patients, from whom the cell lines were developed. Our analysis defines the utility of the most commonly employed WM cell lines as based on their immunophenotype profiles, highlighting unique differences that can be further studied for therapeutic exploit.

Schmidt J, Federmann B, Schindler N, et al.
MYD88 L265P and CXCR4 mutations in lymphoplasmacytic lymphoma identify cases with high disease activity.
Br J Haematol. 2015; 169(6):795-803 [PubMed] Related Publications
Recurrent mutations in MYD88 have been identified in >90% of lymphoplasmacytic lymphoma (LPL). Recently, WHIM (warts, hypogammaglobulinaemia, infections, myelokathexis) syndrome-like mutations in CXCR4 have been described in 28% of LPL cases, and seem to impact clinical presentation and response to therapy. We investigated the presence of the MYD88 L265P mutation in 90 decalcified, formalin-fixed, paraffin-embedded (FFPE) bone marrow (BM) biopsies, including 51 cases of LPL, 14 cases of B-cell chronic lymphocytic leukaemia (CLL), 13 cases of marginal zone lymphoma (MZL) and 12 normal controls. In addition, the C-terminal domain of CXCR4 was sequenced in LPL cases. MYD88 L265P was found in 49/51 (96%) LPL cases and in 1/13 (7·6%) MZL (splenic type), whereas all CLL samples remained negative. The two MYD88 wild type LPL cases were associated with cold agglutinin disease. Mutations in CXCR4 were detected in 17/47 (36·2%) LPL cases, which showed a higher extent of BM infiltration and lower leucocyte counts (P = 0·02), haemoglobin (P = 0·05) and platelet counts (P = 0·01). In conclusion the detection of MYD88 L265P mutation in FFPE samples is reliable and useful for subtyping small B-cell lymphomas in BM biopsies. In addition, the presence of CXCR4 mutations identifies a subgroup of LPL patients with higher disease activity.

Klapper W, Kreipe H
[Diagnostic molecular pathology of lymphatic and myeloid neoplasms].
Pathologe. 2015; 36(2):164-70 [PubMed] Related Publications
Molecular pathology has been an integral part of the diagnostics of tumors of the hematopoietic system substantially longer than for solid neoplasms. In contrast to solid tumors, the primary objective of molecular pathology in hematopoietic neoplasms is not the prediction of drug efficacy but the diagnosis itself by excluding reactive proliferation and by using molecular features for tumor classification. In the case of malignant lymphomas, the most commonly applied molecular tests are those for gene rearrangements for immunoglobulin heavy chains and T-cell receptors. However, this article puts the focus on new and diagnostically relevant assays in hematopathology. Among these are mutations of MYD88 codon 265 in lymphoplasmacytic lymphomas, B-raf V600E in hairy cell leukemia and Stat3 exon 21 in indolent T-cell lymphomas. In myeloproliferative neoplasms, MPL W515, calreticulin exon 9 and the BCR-ABL and JAK2 V617F junctions are the most frequently analyzed differentiation series. In myelodysplastic and myeloproliferative neoplasms, SRSF2, SETBP1 and CSF3R mutations provide important differential diagnostic information. Genes mutated in myelodysplastic syndromes (MDS) are particularly diverse but their analysis significantly improves the differential diagnostics between reactive conditions and MDS. The most frequent changes in MDS include mutations of TET2 and various genes encoding splicing factors.

Izumi M, Tsunemine H, Suzuki Y, et al.
Successful treatment of refractory cold hemagglutinemia in MYD88 L265P mutation-negative Waldenström's macroglobulinemia with bortezomib.
Int J Hematol. 2015; 102(2):238-43 [PubMed] Related Publications
We report here the successful treatment of cold agglutinin-associated refractory hemolysis with bortezomib in a patient with Waldenström's macroglobulinemia (WM). A 78-year-old man was referred to our hospital with cold hemagglutinemia of unknown cause. Laboratory examination revealed a hemoglobin concentration of 6.9 g/dL, serum IgM concentration of 1904 mg/dL, and a titer of cold hemagglutinin of over ×8192. Serum immunoelectrophoresis demonstrated monoclonal protein of the IgM-κ type. A bone marrow aspirate showed many lymphoplasmacytic cells, which were positive for CD19, CD20, CD38, and cytoplasmic μ and κ light chains. A diagnosis of WM-associated cold hemagglutinemia was made. Because of red blood cell transfusion-dependency, we treated him with intravenous fludarabine, oral melphalan-prednisolone, cyclophosphamide, and melphalan, and two courses of R-CHOP in sequence with a marked decrease of serum IgM (928 mg). We then started weekly bortezomib plus dexamethasone (BD) therapy, as he was still transfusion-dependent. Soon after the initiation of BD, he achieved transfusion independence, with a further decrease in serum levels of IgM and marked improvement of anemia. Interestingly, his marrow abnormal lymphocytes were later found not to carry the MYD88 L265P mutation. The successful treatment with bortezomib for WM lacking this mutation is discussed.

Kuiatse I, Baladandayuthapani V, Lin HY, et al.
Targeting the Spleen Tyrosine Kinase with Fostamatinib as a Strategy against Waldenström Macroglobulinemia.
Clin Cancer Res. 2015; 21(11):2538-45 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Waldenström macroglobulinemia (WMG) is a lymphoproliferative disorder characterized by good initial responses to standard therapeutics, but only a minority of patients achieve complete remissions, and most inevitably relapse, indicating a need for novel agents. B-cell receptor signaling has been linked to clonal evolution in WMG, and Spleen tyrosine kinase (Syk) is overexpressed in primary cells, suggesting that it could be a novel and rational target.
EXPERIMENTAL DESIGN: We studied the impact of the Syk inhibitor fostamatinib on BCWM.1 and MWCL-1 WMG-derived cell lines both in vitro and in vivo, as well as on primary patient cells.
RESULTS: In WMG-derived cell lines, fostamatinib induced a time- and dose-dependent reduction in viability, associated with activation of apoptosis. At the molecular level, fostamatinib reduced activation of Syk and Bruton's tyrosine kinase, and also downstream signaling through MAPK kinase (MEK), p44/42 MAPK, and protein kinase B/Akt. As a single agent, fostamatinib induced tumor growth delay in an in vivo model of WMG, and reduced viability of primary WMG cells, along with inhibition of p44/42 MAPK signaling. Finally, fostamatinib in combination with other agents, including dexamethasone, bortezomib, and rituximab, showed enhanced activity.
CONCLUSIONS: Taken together, these data support the translation of approaches targeting Syk with fostamatinib to the clinic for patients with relapsed and possibly even newly diagnosed WMG.

Martinez-Lopez A, Curiel-Olmo S, Mollejo M, et al.
MYD88 (L265P) somatic mutation in marginal zone B-cell lymphoma.
Am J Surg Pathol. 2015; 39(5):644-51 [PubMed] Related Publications
MYD88 L265P is a somatic mutation that has been identified in about 90% of Waldenström macroglobulinemia/lymphoplasmacytic lymphomas (LPLs). It has also been detected in a subset of marginal zone lymphoma (MZL) cases, but the frequency and clinical and histologic features of these mutated MZL cases has only been partially characterized. We have developed a customized TaqMan allele-specific polymerase chain reaction for sensitive detection of this mutation in paraffin-embedded tissue. We analyzed samples from 19 patients with LPL, 88 patients with splenic marginal zone lymphoma (SMZL), 8 patients with nodal marginal zone lymphoma (NMZL), 21 patients with extranodal mucosa-associated lymphoid tissue (MALT), and 2 patients with B-cell lymphoma not otherwise specified. By integrating mutational, histologic, and clinical data, 5 cases were reclassified as LPL. After reclassification, MYD88 L265P was detected in 13/86 (15%) SMZL and in 19/24 LPL (79%) cases. The mutation was absent from NMZL and MALT cases. A strong correlation was found between the presence of an IgM monoclonal paraproteinemia and the MYD88 L265P mutation (P<0.0001). SMZL cases positive for MYD88 L265P were also associated with monoclonal IgM paraproteinemia (4/13 cases; P<0.0283), although with less serum paraproteinemia. They also had a higher frequency of plasmacytic differentiation (9/13) but with no correlation between the presence of mutation and of light chain-restricted plasma cells in tissue. Demonstration of the MYD88 L265 mutation is a valuable tool for the diagnosis of LPL, although some SMZL cases carrying the mutation do not fulfill the diagnostic criteria for LPL.

Paiva B, Corchete LA, Vidriales MB, et al.
The cellular origin and malignant transformation of Waldenström macroglobulinemia.
Blood. 2015; 125(15):2370-80 [PubMed] Related Publications
Although information about the molecular pathogenesis of Waldenström macroglobulinemia (WM) has significantly advanced, the precise cell of origin and the mechanisms behind WM transformation from immunoglobulin-M (IgM) monoclonal gammopathy of undetermined significance (MGUS) remain undetermined. Here, we undertook an integrative phenotypic, molecular, and genomic approach to study clonal B cells from newly diagnosed patients with IgM MGUS (n = 22), smoldering (n = 16), and symptomatic WM (n = 11). Through principal component analysis of multidimensional flow cytometry data, we demonstrated highly overlapping phenotypic profiles for clonal B cells from IgM MGUS, smoldering, and symptomatic WM patients. Similarly, virtually no genes were significantly deregulated between fluorescence-activated cell sorter-sorted clonal B cells from the 3 disease groups. Interestingly, the transcriptome of the Waldenström B-cell clone was highly different than that of normal CD25(-)CD22(+) B cells, whereas significantly less genes were differentially expressed and specific WM pathways normalized once the transcriptome of the Waldenström B-cell clone was compared with its normal phenotypic (CD25(+)CD22(+low)) B-cell counterpart. The frequency of specific copy number abnormalities [+4, del(6q23.3-6q25.3), +12, and +18q11-18q23] progressively increased from IgM MGUS and smoldering WM vs symptomatic WM (18% vs 20% and 73%, respectively; P = .008), suggesting a multistep transformation of clonal B cells that, albeit benign (ie, IgM MGUS and smoldering WM), already harbor the phenotypic and molecular signatures of the malignant Waldenström clone.

Cao Y, Hunter ZR, Liu X, et al.
CXCR4 WHIM-like frameshift and nonsense mutations promote ibrutinib resistance but do not supplant MYD88(L265P) -directed survival signalling in Waldenström macroglobulinaemia cells.
Br J Haematol. 2015; 168(5):701-7 [PubMed] Related Publications
CXCR4(WHIM) frameshift and nonsense mutations follow MYD88(L265P) as the most common somatic variants in Waldenström Macroglobulinaemia (WM), and impact clinical presentation and ibrutinib response. While the nonsense (CXCR4(S338X) ) mutation has been investigated, little is known about CXCR4 frameshift (CXCR4(FS) ) mutations. We engineered WM cells to express CXCR4(FS) mutations present in patients, and compared their CXCL12 (SDF-1a) induced signalling and ibrutinib sensitivity to CXCR4(wild-type (WT)) and CXCR4(S338X) cells. Following CXCL12 stimulation, CXCR4(FS) and CXCR4(S338X) WM cells showed impaired CXCR4 receptor internalization, and enhanced AKT1 (also termed AKT) and MAPK1 (also termed ERK) activation versus CXCR(WT) cells (P < 0·05), though MAPK1 activation was more prolonged in CXCR4(S338X) cells (P < 0·05). CXCR4(FS) and CXCR4(S338X) cells, but not CXCR4(WT) cells, were rescued from ibrutinib-triggered apoptosis by CXCL12 that was reversed by AKT1, MAPK1 or CXCR4 antagonists. Treatment with an inhibitor that blocks MYD88(L265P) signalling triggered similar levels of apoptosis that was not abrogated by CXCL12 treatment in CXCR4(WT) and CXCR4(WHIM) cells. These studies show a functional role for CXCR4(FS) mutations in WM, and provide a framework for the investigation of CXCR4 antagonists with ibrutinib in CXCR4(WHIM) -mutated WM patients. Direct inhibition of MYD88(L265P) signalling overcomes CXCL12 triggered survival effects in CXCR4(WHIM) -mutated cells supporting a primary role for this survival pathway in WM.

Petrikkos L, Kyrtsonis MC, Roumelioti M, et al.
Clonotypic analysis of immunoglobulin heavy chain sequences in patients with Waldenström's macroglobulinemia: correlation with MYD88 L265P somatic mutation status, clinical features, and outcome.
Biomed Res Int. 2014; 2014:809103 [PubMed] Free Access to Full Article Related Publications
We performed IGH clonotypic sequence analysis in WM in order to determine whether a preferential IGH gene rearrangement was observed and to assess IGHV mutational status in blood and/or bone marrow samples from 36 WM patients. In addition we investigated the presence of MYD88 L265P somatic mutation. After IGH VDJ locus amplification, monoclonal VDJ rearranged fragments were sequenced and analyzed. MYD88 L265P mutation was detected by AS-PCR. The most frequent family usage was IGHV3 (74%); IGHV3-23 and IGHV3-74 segments were used in 26% and 17%, respectively. Somatic hypermutation was seen in 91% of cases. MYD88 L265P mutation was found in 65,5% of patients and absent in the 3 unmutated. These findings did not correlate with clinical findings and outcome. Conclusion. IGH genes' repertoire differed in WM from those observed in other B-cell disorders with a recurrent IGHV3-23 and IGHV3-74 usage; monoclonal IGHV was mutated in most cases, and a high but not omnipresent prevalence of MYD88 L265P mutation was observed. In addition, the identification of 3 patients with unmutated IGHV gene segments, negative for the MYD88 L265P mutation, could support the hypothesis that an extra-germinal B-cell may represent the originating malignant cell in this minority of WM patients.

Poulain S, Boyle EM, Roumier C, et al.
MYD88 L265P mutation contributes to the diagnosis of Bing Neel syndrome.
Br J Haematol. 2014; 167(4):506-13 [PubMed] Related Publications
Bing-Neel syndrome (BNS), a rare neurological syndrome associated with Waldenström macroglobulinaemia (WM), is a direct involvement of the central nervous system by lymphoplasmacytoid cells characterized with an adverse prognostic. The MYD88 L265P mutation has been identified in the vast majority of patients with WM. The diagnosis of BNS is often challenging because of the variety of clinical presentations associated with difficult histological techniques. We hypothesized that identification of MYD88 L265P mutation in the cerebrospinal fluid (CSF) would contribute to the diagnosis of BNS in addition to imaging, flow cytometry and cytology. We identified MYD88 L265P mutation in the CSF and the bone marrow of all cases of BNS using quantitative polymerase chain reaction qPCR and Sanger sequencing. Copy neutral loss of heterozygosity including MYD88 was observed in one case. No mutation of CXCR4, CD79A and CD79B was observed in parallel. We further showed that monitoring the quantitative expression of MYD88 L265P mutation might be a useful molecular tool to monitor response to chemotherapy using qPCR. In conclusion, identification of MYD88 L265P mutation might be a new molecular-based biomarker tool to add to the diagnostic and monitoring armamentarium for BNS.

Kuppusamy H, Ogmundsdottir HM, Baigorri E, et al.
Inherited polymorphisms in hyaluronan synthase 1 predict risk of systemic B-cell malignancies but not of breast cancer.
PLoS One. 2014; 9(6):e100691 [PubMed] Free Access to Full Article Related Publications
Genetic variations in the hyaluronan synthase 1 gene (HAS1) influence HAS1 aberrant splicing. HAS1 is aberrantly spliced in malignant cells from multiple myeloma (MM) and Waldenstrom macroglobulinemia (WM), but not in their counterparts from healthy donors. The presence of aberrant HAS1 splice variants predicts for poor survival in multiple myeloma (MM). We evaluated the influence of inherited HAS1 single nucleotide polymorphisms (SNP) on the risk of having a systemic B cell malignancy in 1414 individuals compromising 832 patients and 582 healthy controls, including familial analysis of an Icelandic kindred. We sequenced HAS1 gene segments from 181 patients with MM, 98 with monoclonal gammopathy of undetermined significance (MGUS), 72 with Waldenstrom macroglobulinemia (WM), 169 with chronic lymphocytic leukemia (CLL), as well as 34 members of a monoclonal gammopathy-prone Icelandic family, 212 age-matched healthy donors and a case-control cohort of 295 breast cancer patients with 353 healthy controls. Three linked single nucleotide polymorphisms (SNP) in HAS1 intron3 are significantly associated with B-cell malignancies (range p = 0.007 to p = 10(-5)), but not MGUS or breast cancer, and predict risk in a 34 member Icelandic family (p = 0.005, Odds Ratio = 5.8 (OR)), a relatively homogeneous cohort. In contrast, exon3 SNPs were not significantly different among the study groups. Pooled analyses showed a strong association between the linked HAS1 intron3 SNPs and B-cell malignancies (OR = 1.78), but not for sporadic MGUS or for breast cancer (OR<1.0). The minor allele genotypes of HAS1 SNPs are significantly more frequent in MM, WM, CLL and in affected members of a monoclonal gammopathy-prone family than they are in breast cancer, sporadic MGUS or healthy donors. These inherited changes may increase the risk for systemic B-cell malignancies but not for solid tumors.

Kim JA, Im K, Park SN, et al.
MYD88 L265P mutations are correlated with 6q deletion in Korean patients with Waldenström macroglobulinemia.
Biomed Res Int. 2014; 2014:363540 [PubMed] Free Access to Full Article Related Publications
Waldenström macroglobulinemia (WM) is a malignant lymphoplasma-proliferative disorder with IgM monoclonal gammopathy. A recent whole-genome study identified MYD88 L265P as the key mutation in WM. We investigated MYD88 mutations in conjunction with cytogenetic study in 22 consecutive Korean WM patients. Conventional G-banding and interphase fluorescence in situ hybridization (FISH) were performed at regions including 6q21 using bone marrow (BM) aspirates. Sixteen patients were subjected to Sanger sequencing-based MYD88 mutation study. Five patients (28%) showed cytogenetic aberrations in G-banding. The incidence of 6q21 deletion was 17% by conventional G-banding and 37% by FISH. Ten patients (45%) showed cytogenetic aberrations using FISH: 6q deletion in eight (37%) and IGH rearrangement in four (18%). Two patients had both the 6q deletion and IGH rearrangement, and two had only the IGH rearrangement. Eleven patients (69%) presented with the MYD88 L265P mutation. MYD88 mutations were significantly associated with the presence of 6q deletions (P = 0.037). Six patients with the 6q deletion for whom sequencing was possible were found to harbor MYD88 mutations. The MYD88 L265P mutation was also associated with increased lymphocyte burden in BM biopsy. This is the first report of high frequency MYD88 L265P mutations in Korean WM patients.

Capaldi IB, May AM, Schmitt-Graeff A, et al.
Detection of MYD88 L265P mutations in formalin-fixed and decalcified BM biopsies from patients with lymphoplasmacytic lymphoma.
Exp Mol Pathol. 2014; 97(1):57-65 [PubMed] Related Publications
The diagnosis of bone marrow (BM) infiltration by Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) poses a diagnostic challenge in hematopathology. No definitive morphology or immunophenotype is able to distinguish between infiltration of paraffin-embedded BM sections by WM/LPL and other indolent lymphomas, in particular those of the splenic marginal zone (SMZL) which may also show plasmacytic maturation. An oncogenic gain-of-function mutation (L265P) in the human MYD88 gene has been found to be present in most cases of WM/LPL, yet is absent in most other cases of B-cell chronic lymphoproliferative disorders (LPD), including SMZL. Here, we compare two newly developed diagnostic protocols for detection of this mutation in paraffin-embedded archival tissues which are particularly applicable to decalcified BM biopsies. Sanger sequencing can easily detect levels of BM infiltration above 15% by WM lymphoplasmacytic cells, while the allele-specific PCR can detect the L265P mutation in BM infiltrations below 1% of lymphoma cells. We show that these methods are easily applicable to archival BM specimens and markedly improve diagnostic accuracy of BM infiltrations by indolent B-cell lymphomas.

Patkar N, Subramanian PG, Deshpande P, et al.
MYD88 mutant lymphoplasmacytic lymphoma/Waldenström macroglobulinemia has distinct clinical and pathological features as compared to its mutation negative counterpart.
Leuk Lymphoma. 2015; 56(2):420-5 [PubMed] Related Publications
In a first series from India, we report 32 cases of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) over 7 years. Here, we analyzed 32 patients with LPL/WM for MYD88 L265P mutation and correlated mutation staus with hematological and biochemical parameters and also with the International Prognostic Scoring System (ISSWM) and treatment response. Twenty-seven out of 32 cases of LPL/WM (84.3%) harbored the MYD88 L265P mutation. MYD88 wild-type WM was associated with a lower number of tumor cells (p<0.01) and older age (p=0.02) and a lower ISSWM score at presentation (p=0.03) as compared to mutated LPL/WM. On evaluation of response (n=23), 44.4% of patients with MYD88 mutated LPL/WM had progressive disease, whereas no patient in the MYD88 unmutated group changed their baseline status. We confirm the high frequency of MYD88 mutations in LPL/WM. Although the number of MYD88 wild-type cases was limited, our data indicate that MYD88 may represent an adverse prognostic marker for LPL/WM.

Zhou Y, Liu X, Xu L, et al.
Transcriptional repression of plasma cell differentiation is orchestrated by aberrant over-expression of the ETS factor SPIB in Waldenström macroglobulinaemia.
Br J Haematol. 2014; 166(5):677-89 [PubMed] Related Publications
In Waldenström macroglobulinaemia (WM), the mechanism(s) responsible for repression of B-cell differentiation remains unknown. We found that expression of SPIB and ID2 were significantly increased and decreased, respectively, in WM lymphoplasmacytic cells (LPC). Ectopic expression of SPIB in healthy donor CD19(+) cells inhibited plasmacytic differentiation in conjunction with decreased transcription of IRF4 and XBP1 spliced form. In primary WM LPC, knock-down of SPIB induced plasmacytic differentiation in conjunction with increased transcription of PRDM1, XBP1 spliced form, IRF4 and ID2. Knock-down of SPIB also led to decreased BCL2 expression. Given that SPIB is a direct target of POU2AF1 (OBF1) in complex with POU2F2 or POU2F1, we next examined their expression in WM LPC. POU2F2 transcription, as well as POU2F2 and POU2AF1 protein expression was higher in WM LPC. Ectopic expression of POU2F2 in healthy donor CD19(+) cells induced transcription of SPIB and suppressed transcription of PRDM1 and IRF4. Chromatin immunoprecipitation analysis in BCWM.1 WM cells confirmed binding of POU2F2 and POU2AF1 in SPIB and ID2 promoters. These findings establish a molecular hierarchy among POU2F2, SPIB and ID2 during B-cell differentiation, and suggest that aberrant expression of these transcription factors plays an important role in arresting plasmacytic differentiation in WM.

Lenz G
Waldenstrom macroglobulinemia: genetics dictates clinical course.
Blood. 2014; 123(18):2750-1 [PubMed] Related Publications
In this issue of Blood, Treon and colleagues provide strong evidence that mutations in MYD88 and CXCR4 dictate clinical presentation and survival in Waldenström macroglobulinemia (WM).

Sakata-Yanagimoto M, Enami T, Yokoyama Y, Chiba S
Disease-specific mutations in mature lymphoid neoplasms: recent advances.
Cancer Sci. 2014; 105(6):623-9 [PubMed] Free Access to Full Article Related Publications
Mature lymphoid neoplasms (MLN) are clinically and pathologically more complex than precursor lymphoid neoplasms. Until recently, molecular characterization of MLN was mainly based on cytogenetics/fluorescence in situ hybridization, allele copy number, and mRNA expression, approaches that yielded scanty gene mutation information. Use of massive parallel sequencing technologies has changed this outcome, and now many gene mutations have been discovered. Some of these are considerably frequent in, and substantially specific to, distinct MLN subtypes, and occur at single or several hotspots. They include the V600E BRAF mutation in hairy cell leukemia, the L265P MYD88 mutation in Waldenström macroglobulinemia, the G17V RHOA mutation in angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, not otherwise specified, and the Y640F//D661Y/V/H/I//N647I STAT3 mutations in T-cell large granular lymphocytic leukemia. Detecting these mutations is highly valuable in diagnosing MLN subtypes. Defining these mutations also sheds light on the molecular pathogenesis of MLN, furthering development of molecular targeting therapies. In this review, we focus on the disease-specific gene mutations in MLN discovered by recent massive sequencing technologies.

Landgren O, Tageja N
MYD88 and beyond: novel opportunities for diagnosis, prognosis and treatment in Waldenström's Macroglobulinemia.
Leukemia. 2014; 28(9):1799-803 [PubMed] Related Publications
Waldenström's Macroglobulinemia (WM) is a rare disease of the elderly with a median age of 63-68 years at diagnosis. Despite recent progress in biological insights and therapeutics, WM remains clinically challenging to diagnose and is difficult to manage with significant morbidity and lack of established curative therapies. Recently, the use of whole-genome sequencing has helped to identify a highly recurrent somatic mutation, myeloid differentiation factor 88 [MYD88] L265P in WM. This has fueled major interest in the field and as newer evidence accumulates, it is clear that that discovery of MYD88 L265P mutation may represent an important breakthrough in understanding the pathogenesis of WM and lymphoproliferative disorders. Recent scientific work in this field has also guided the identification of new targets such as CXCR4 and PI3K-delta that may have major implications in the future treatment of WM. This review discusses the role of MYD88 L265P mutations as well as targets beyond MYD88 in the setting of pathogenesis and development of future rational therapeutic trials focusing on patients diagnosed with WM.

Treon SP, Cao Y, Xu L, et al.
Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenstrom macroglobulinemia.
Blood. 2014; 123(18):2791-6 [PubMed] Related Publications
Whole genome sequencing has revealed activating somatic mutations in MYD88 (L265P) and CXCR4 in Waldenström macroglobulinemia (WM). CXCR4 somatic mutations in WM are the first ever reported in human cancer and are similar to nonsense (NS) and frameshift (FS) germline mutations found in warts, hypogammaglobulinemia, infections and myelokathexis (WHIM) syndrome. We genotyped lymphoplasmacytic cells from 175 WM patients and observed significantly higher bone marrow (BM) disease involvement, serum immunoglobulin-M levels, and symptomatic disease requiring therapy, including hyperviscosity syndrome in those patients with MYD88(L265P)CXCR4(WHIM/NS) mutations (P < .03). Patients with MYD88(L265P)CXCR4(WHIM/FS) or MYD88(L265P)CXCR4(WILDTYPE (WT)) had intermediate BM and serum immunoglobulin-M levels; those with MYD88(WT)CXCR4(WT) showed lowest BM disease burden. Fewer patients with MYD88(L265P) and CXCR4(WHIM/FS or NS) vs MYD88(L265P)CXCR4(WT) presented with adenopathy (P < .01), further delineating differences in disease tropism based on CXCR4 status. Neither MYD88 nor CXCR4 mutations correlated with SDF-1a (RS1801157) polymorphisms in 54 patients who were genotyped for these variants. Unexpectedly, risk of death was not impacted by CXCR4 mutation status, but by MYD88(WT) status (hazard ratio 10.54; 95% confidence interval 2.4-46.2, P = .0018). Somatic mutations in MYD88 and CXCR4 are important determinants of clinical presentation and impact overall survival in WM. Targeted therapies directed against MYD88 and/or CXCR4 signaling may provide a personalized treatment approach to WM.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. Waldenstrom's Macroglobulinemia, Cancer Genetics Web: http://www.cancer-genetics.org/waldenstroms.html Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 10 March, 2017     Cancer Genetics Web, Established 1999