A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenström macroglobulinemia.

@article{Yang2013AMI,
  title={A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenstr{\"o}m macroglobulinemia.},
  author={G. Yang and Y. Zhou and Xia Liu and Lian Xu and Yanglin Cao and R. Manning and C. Patterson and S. Buhrlage and N. Gray and Y. Tai and K. Anderson and Z. Hunter and S. Treon},
  journal={Blood},
  year={2013},
  volume={122 7},
  pages={
          1222-32
        }
}
Myeloid differentiation factor 88 (MYD88) L265P somatic mutation is highly prevalent in Waldenström macroglobulinemia (WM) and supports malignant growth through nuclear factor κB (NF-κB. [...] Key Result By lentiviral knockdown or use of a MYD88 inhibitor, decreased phosphorylation of the NF-κB gatekeeper IκBα and survival occurred in MYD88 L265P-expressing WM cells. Conversely, WM cells engineered to overexpress MYD88 L265P showed enhanced survival.Expand
HCK is a survival determinant transactivated by mutated MYD88, and a direct target of ibrutinib.
TLDR
It is observed that mutated MYD88 WM and ABC DLBCL cell lines, as well as primary WM cells show enhanced hematopoietic cell kinase (HCK) transcription and activation, and that HCK is activated by interleukin 6 (IL-6). Expand
LYMPHOID NEOPLASIA MYD 88-independent growth and survival effects of Sp 1 transactivation in Waldenström macroglobulinemia
Gene expression and proteomic studies have advanced our understanding of Waldenström macroglobulinemia (WM) and identified potential therapeutic targets.Whole-genome sequencing identified somaticExpand
Targeting Myddosome Signaling in Waldenström's Macroglobulinemia with the Interleukin-1 Receptor-Associated Kinase 1/4 Inhibitor R191
Purpose: Waldenström's macroglobulinemia is an incurable lymphoproliferative disorder driven by an L265P mutation in the myeloid differentiation primary response gene 88 (MYD88), which activatesExpand
Disrupting myddosome assembly in diffuse large B-cell lymphoma cells using the MYD88 dimerization inhibitor ST2825
TLDR
Evidence is provided that the synthetic peptidomimetic compound ST2825, which targets myddosome assembly, may serve as a pharmacological inhibitor in patients with L265P DLBCL, and other B-cell neoplasms driven by activated MYD88 signaling. Expand
SYK is activated by mutated MYD88 and drives pro-survival signaling in MYD88 driven B-cell lymphomas
TLDR
The spectrum of mutated MYD88 pro-survival signaling is extended to include SYK directed BCR cross talk in MyD88 -mutated lymphomas, providing a framework for the clinical investigation of ibrutinib with SYK inhibitors in MYD 88 -mutation lymphomas. Expand
Human MYD88L265P is insufficient by itself to drive neoplastic transformation in mature mouse B cells.
TLDR
In mice, human MYD88L265P promotes development of a non-clonal, low-grade B-cell lymphoproliferative disorder with several clinicopathologic features that resemble human LPL/WM, including expansion of lymphoplasmacytoid cells, increased serum immunoglobulin M (IgM) concentration, rouleaux formation, and proinflammatory signaling that progresses sporadically to clonal, high-grade DLBCL. Expand
Waldenstrom ' s macroglobulinemia MYD 88-independent growth and survival effects of Sp 1 transactivation in
Sp1 transcription factor controls a pleiotropic group of genes and its aberrant activation has been reported in number of malignancies including multiple myeloma. Here we investigated and report itsExpand
Insights into the genomic landscape of MYD88 wild-type Waldenström macroglobulinemia.
TLDR
Overall survival was adversely affected by mutations in DNA damage response in MYD88 WT WM patients, and mechanistic insights for disease transformation, decreased ibrutinib activity, and novel drug approaches for this population are provided. Expand
MYD88-independent growth and survival effects of Sp1 transactivation in Waldenstrom macroglobulinemia.
TLDR
Results demonstrate Sp1 as an important transcription factor that regulates proliferation and survival of WM cells independent of MYD88 pathway activation, and provide preclinical rationale for clinical development of TMP in WM alone or in combination with inhibitors of MYd88 pathway. Expand
Response to ibrutinib in a patient with IgG lymphoplasmacytic lymphoma carrying the MYD88 L265P gene mutation
TLDR
The first report of a patient with MYD88-mutated IgG LPL who underwent salvage therapy with ibrutinib is presented, a nine-year lapse off therapy with normal serum IgG levels. Expand
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References

SHOWING 1-10 OF 36 REFERENCES
Oncogenically active MYD88 mutations in human lymphoma
TLDR
The dependence of ABC DLBCLs on MYD88, an adaptor protein that mediates toll and interleukin (IL)-1 receptor signalling, is described and the development of inhibitors of IRAK4 kinase and other components of this pathway for the treatment of tumours bearing oncogenic MyD88 mutations are supported. Expand
Prevalence and clinical significance of the MYD88 (L265P) somatic mutation in Waldenstrom's macroglobulinemia and related lymphoid neoplasms.
TLDR
Findings indicate that the allele-specific PCR developed is a useful diagnostic tool for patients with Waldenström's macroglobulinemia or IgM-MGUS, and may therefore also represent a useful prognostic marker. Expand
MYD88 L265P in Waldenström macroglobulinemia, immunoglobulin M monoclonal gammopathy, and other B-cell lymphoproliferative disorders using conventional and quantitative allele-specific polymerase chain reaction.
TLDR
These studies identify MYD88 L265P as a widely present mutation in WM and IgM MGUS patients using highly sensitive and specific AS-PCR assays with potential use in diagnostic discrimination and/or response assessment. Expand
MYD88 L265P is a marker highly characteristic of, but not restricted to, Waldenström’s macroglobulinemia
TLDR
Among WM and IgM-MGUS, MyD88 L265P mutation was associated with some differences in clinical and biological characteristics, although usually minor; wild-type MYD88 cases had smaller M-component and less IGHV3–23 gene selection; these small differences did not lead to different time to first therapy, response to treatment or progression-free or overall survival. Expand
Bruton’s Tyrosine Kinase Mediates NF-κB Activation and B Cell Survival by B Cell-Activating Factor Receptor of the TNF-R Family1
TLDR
It is shown that Bruton’s tyrosine kinase (Btk) also couples the receptor for B cell-activating factor of the TNF family (BAFF-R) to the NF-κB pathway, suggesting that Btk regulates B cell survival by directly regulating the classical NF-kkB pathway under both BCR and BAff-R. Expand
Targeting NF-kappaB in Waldenstrom macroglobulinemia.
TLDR
It is demonstrated that perifosine and bortezomib both targeted NF-kappaB through its recruitment to the promoter of its target gene IkappaB using chromatin immunoprecipitation assay, which led to synergistic cytotoxicity in Waldenstrom macroglobulinemia cells that was mediated through a combined reduction of the PI3K/Akt and ERK signaling pathways. Expand
MYD88 L265P somatic mutation in Waldenström's macroglobulinemia.
TLDR
MYD88 L265P is a commonly recurring mutation in patients with Waldenström's macroglobulinemia that can be useful in differentiating WaldenStröm’s macrogalobulinesia and non-IgM LPL from B-cell disorders that have some of the same features. Expand
Bruton's Tyrosine Kinase Links the B Cell Receptor to Nuclear Factor κb Activation
TLDR
Bruton's tyrosine kinase (BTK) is essential for activation of NF-κB via the B cell receptor, and the ability of BTK to regulate the nuclear factor (NF)-κB/Rel family of transcription factors, as the activation of these factors is required for a B cell response to mIgM is examined. Expand
Bruton ’ s Tyrosine Kinase Links the B Cell Receptor to Nuclear Factor k B Activation
The recognition of antigen by membrane immunoglobulin M (mIgM) results in a complex series of signaling events in the cytoplasm leading to gene activation. Bruton’s tyrosine kinase (BTK), a member ofExpand
IGHV gene features and MYD88 L265P mutation separate the three marginal zone lymphoma entities and Waldenström macroglobulinemia/lymphoplasmacytic lymphomas
TLDR
The results demonstrate that the history of antigen exposure of the four entities studied was different and MYD88 L265P was specifically associated with WM/LPLs, which may thus be functionally associated with constitutive nuclear factor-κB activation. Expand
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