Waldenström Macroglobulinemia: Clinical and Immunological Aspects, Natural History, Cell of Origin, and Emerging Mouse Models

• Transcription profiles associated with mutated MYD88, CXCR4, ARID1A, abnormal cytogenetics including 6q2, and familial WM are described.• Mutated CXCR4 profiles show impaired expression of the tumor suppressor response induced by MYD88 L265P and also G-protein/MAPK inhibitors.Whole-genome sequencing has identified highly prevalent somatic mutations including MYD88, CXCR4, and ARID1A in Waldenström macroglobulinemia (WM). The impact of these and other somatic mutations on transcriptional regulation in WM remains to be clarified. We performed next-generation transcriptional profiling in 57 WM patients and compared findings to healthy donor B cells. Compared with healthy donors, WM patient samples showed greatly enhanced expression of the VDJ recombination genes DNTT, RAG1, and RAG2, but not AICDA. Genes related to CXCR4 signaling were also upregulated and included CXCR4, CXCL12, and VCAM1 regardless of CXCR4 mutation status, indicating a potential role for CXCR4 signaling in all WM patients. The WM transcriptional profile was equally dissimilar to healthy memory B cells and circulating B cells likely due increased differentiation rather than cellular origin. The profile for CXCR4 mutations corresponded to diminished B-cell differentiation and suppression of tumor suppressors upregulated by MYD88 mutations in a manner associated with the suppression of TLR4 signaling relative to those mutated for MYD88 alone. Promoter methylation studies of top findings failed to explain this suppressive effect but identified aberrant methylation patterns in MYD88 wild-type patients. CXCR4 and MYD88 transcription were negatively correlated, demonstrated allele-specific transcription bias, and, along with CXCL13, were associated with bone marrow disease involvement. Distinct gene expression profiles for patients with wild-type MYD88, mutated ARID1A, familial predisposition to WM, chr6q deletions, chr3q amplifications, and trisomy 4 are also described. The findings provide novel insights into the molecular pathogenesis and opportunities for targeted therapeutic strategies for WM. (Blood. 2016;128(6):827-838)

show abstract

“…The latter represent the B-cell population from where most cases of WM are thought to be derived. 18,19 Methods…”

Section: Introductionmentioning

confidence: 99%

Transcriptome sequencing reveals a profile that corresponds to genomic variants in Waldenström macroglobulinemia

Hunter

Liu

Yang

et al. 2016

Blood

View full text Add to dashboard Cite

show abstract

“…In a study by Ghobrial et al with 26 treatment-naïve WM patients, 6 cycles of bortezomib combined with rituximab showed ORR 100%, 1-year PFS and OS rates of 75% and 96%, respectively 39 . RCyD combination showed a median PFS of 35 months and 5-year OS rate of 62% 28,31 . Similar to RCyD, bortezomib, dexamethasone, and rituximab (BDR) combination in two studies showed ORR 90–96%, PFS rate 40–80%, and OS rate 80–100% with significant improvement in BM involvement and serum IgM levels 40,41 .…”

Section: Managementsmentioning

confidence: 98%

“…Also, careful interpretation is needed to differentiate IgM flare from lack of response or disease progression. Plasmapheresis is suggested in patients with high IgM (>4000mg/dL) or hyperviscosity symptoms to prevent IgM flare 28 . Of note, late intolerance to rituximab occurs in 10–15% of cases.…”

Section: Managementsmentioning

confidence: 99%

“…Therapies that are currently being investigated through phase II clinical trials include single or combination therapies of monoclonal antibodies, proteasome inhibitors, immunomodulatory agents, PI3K/Akt/mTOR pathway inhibitors, BTK inhibitors, and a histone deacetylase inhibitor, while others are still in early developmental stages 28 .…”

Section: Future Perspectivementioning

confidence: 99%

See 1 more Smart Citation

Waldenström Macroglobulinemia: Review of Pathogenesis and Management

Yun

Johnson

Okolo

et al. 2017

Clinical Lymphoma Myeloma and Leukemia

View full text Add to dashboard Cite

Waldenström macroglobulinemia (WM) is a low-grade B-cell clonal disorder characterized by lymphoplasmacytic bone marrow involvement associated with monoclonal immunoglobulin M (IgM). Although WM remains to be an incurable disease with a heterogeneous clinical course, the recent discovery of mutations in the MYD88 and CXCR4 genes further enhanced our understanding of its pathogenesis. Development of new therapies including monoclonal antibodies, proteasome inhibitors, and Bruton’s tyrosine kinase inhibitors have made the management of WM increasingly complex. Treatment should be tailored to the individual patient while considering many clinical factors. The clinical outcomes are expected to continue to improve given the emergence of novel therapeutics and better understanding of the underlying pathogenesis.

show abstract

“…10 Further therapeutic advances and the closure of pathophysiological knowledge gaps may depend in no small measure on the development of an accurate, genetically engineered mouse model (GEMM) of human IgM + LPL in which WM-like neoplasms develop predictably with short latency and high tumor incidence. 11 …”

Section: Introductionmentioning

confidence: 99%

Transgenic mouse model of IgM+ lymphoproliferative disease mimicking Waldenström macroglobulinemia

Tompkins

Sompallae

et al. 2016

Blood Cancer Journal

View full text Add to dashboard Cite

Waldenström macroglobulinemia (WM) is a low-grade incurable immunoglobulin M+ (IgM+) lymphoplasmacytic lymphoma for which a genetically engineered mouse model of de novo tumor development is lacking. On the basis of evidence that the pro-inflammatory cytokine, interleukin 6 (IL6), and the survival-enhancing oncoprotein, B cell leukemia 2 (BCL2), have critical roles in the natural history of WM, we hypothesized that the enforced expression of IL6 and BCL2 in mice unable to perform immunoglobulin class switch recombination may result in a lymphoproliferative disease that mimics WM. To evaluate this possibility, we generated compound transgenic BALB/c mice that harbored the human BCL2 and IL6 transgenes, EμSV-BCL2-22 and H2-Ld-hIL6, on the genetic background of activation-induced cytidine deaminase (AID) deficiency. We designated these mice BCL2+IL6+AID− and found that they developed—with full genetic penetrance (100% incidence) and suitably short latency (93 days median survival)—a severe IgM+ lymphoproliferative disorder that recapitulated important features of human WM. However, the BCL2+IL6+AID− model also exhibited shortcomings, such as low serum IgM levels and histopathological changes not seen in patients with WM, collectively indicating that further refinements of the model are required to achieve better correlations with disease characteristics of WM.

show abstract

Waldenström Macroglobulinemia: Clinical and Immunological Aspects, Natural History, Cell of Origin, and Emerging Mouse Models

Cited by 20 publications

References 253 publications

Transcriptome sequencing reveals a profile that corresponds to genomic variants in Waldenström macroglobulinemia

Transcriptome sequencing reveals a profile that corresponds to genomic variants in Waldenström macroglobulinemia

Waldenström Macroglobulinemia: Review of Pathogenesis and Management

Transgenic mouse model of IgM+ lymphoproliferative disease mimicking Waldenström macroglobulinemia

Contact Info

Product

Resources

About