MyD88-loaded EVs were detected in the bone marrow aspirates of WM patients thus establishing the physiological role of EVs for MyD88<sup>L265P</sup> transmission and shaping of the proinflammatory microenvironment.
Identification of highly recurrent activating somatic mutation in MYD88 has improved our understanding of the pathogenesis of Waldenström macroglobulinemia and has therapeutic implications.
MYD88L265P was absent in paired normal tissue samples from patients with Waldenström's macroglobulinemia or non-IgM LPL and in B cells from healthy donors and was absent or rarely expressed in samples from patients with multiple myeloma, marginal-zone lymphoma, or IgM monoclonal gammopathy of unknown significance.
The aim of our study was to establish an unlabeled probe genotyping approach for rapid detection of the MYD88L265P mutation in the differential diagnosis of Waldenstrӧm macroglobulinemia patients.
This review discusses the role of MYD88L265P 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.
Although the absence of the MyD88L265P somatic mutation in our SS cohort does not exclude a common germline susceptibility gene in SS, it might suggest a distinct operating pathogenetic mechanism in SS-related lymphoma compared with WM and other hematological malignancies.
The findings support that HCK expression and activation is triggered by mutated MYD88, supports the growth and survival of mutated MYD88WM and ABC DLBCL cells, and is a direct target of ibrutinib.
In conclusion, in this small case series we showed that MYD88L265P mutation analysis could serve as a useful adjunct in distinguishing benign from lymphomatous PE in patients with LPL.
Recent molecular studies have identified mutations in the MYD88 and CXCR4 genes as early events in the pathogenesis of IgM MGUS and Waldenström's macroglobulinemia.
This review discusses the molecular and biological mechanisms underlying MYD88 mutations in LPL/WM, the role of MYD88 mutations as molecular biomarker for the refinement of diagnosis and the improvement classification of LPL/WM, and novel targeted therapeutic strategies for LPL/WM based on the pharmacological manipulation of MYD88 signaling to which this lymphoma is addicted.
These studies show the feasibility for detecting MYD88 L265P by PB examination, and the potential for PB MYD88L265P ΔCt use in the diagnosis and management of WM patients.
<b>Purpose:</b> Everolimus inhibits mTOR, a component of PI3K/AKT prosurvival signaling triggered by MYD88 and CXCR4-activating mutations in Waldenstrom macroglobulinemia.<b>Experimental design:</b> We evaluated everolimus in a prospective, multicenter study of 33 symptomatic, previously untreated Waldenstrom macroglobulinemia patients.
Whole-genome sequencing has revealed MYD88L265P and CXCR4 mutations (CXCR4(mut)) as the most prevalent somatic mutations in Waldenström macroglobulinemia.
The diagnosis of Waldenström Macroglobulinaemia (WM)/lymphoplasmacytic lymphoma (LPL) remains one of exclusion because other B-cell lymphoproliferative disorders (B-LPD), such as marginal zone lymphoma (MZL), can fulfil similar criteria, including MYD88L265P mutation.
We identified the MYD88L265P 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).
Abnormalities that affect myeloid differentiation primary response 88 (MYD88)--interleukin-1 receptor-associated kinase 4 (IRAK4) and nuclear factor kappa B (NF-κB) signaling pathways were found in a significant proportion of WM cases, which suggest their relevance in the pathogenesis of the disease and opening new avenues that may be a guide to design novel therapeutic approaches.
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.
The diagnosis of WM is established by the presence of lymphoplasmacytic lymphoma in the bone marrow or other organs, a monoclonal IgM paraproteinemia and the recurrent MYD88L265P somatic mutation.