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Summary: MYD88 mutations are present in 95% of Waldenstrom Macroglobulinaemia (WM) patients, and support diagnostic discrimination from other IgM‐secreting B‐cell malignancies. Diagnostic discrimination can be difficult among suspected wild‐type MYD88 (MYD88WT) WM cases. We systematically reviewed the clinical, pathological and laboratory studies for 64 suspected MYD88WT WM patients. World Health Organization and WM consensus guidelines were used to establish clinicopathological diagnosis. Up to 30% of suspected MYD88WT WM cases had an alternative clinicopathological diagnosis, including IgM multiple myeloma. The estimated 10‐year survival was 73% (95% confidence interval [CI] 52–86%) for MYD88WTversus 90% (95% CI 82–95%) for mutated (MYD88MUT) WM patients (Log‐rank P < 0·001). Multivariate analysis only showed MYD88 mutation status (P < 0·001) as a significant determinant for overall survival. Diffuse large B‐cell lymphoma (DLBCL) was diagnosed in 7 (15·2%) and 2 (0·76%) of MYD88WT and MYD88MUT patients, respectively (Odds ratio 23·3; 95% CI 4·2–233·8; P < 0·001). Overall survival was shorter among MYD88WT patients with an associated DLBCL event (Log‐rank P = 0·08). The findings show that among suspected MYD88WT WM cases, an alternative clinicopathological diagnosis is common and can impact clinical care. WM patients with MYD88WT disease have a high incidence of associated DLBCL events and significantly shorter survival versus those with MYD88MUT disease. [ABSTRACT FROM AUTHOR]

Summary: Little is known about TP53 mutations in Waldenström Macroglobulinaemia (WM). We evaluated 265 WM patients for TP53 mutations by next‐generation sequencing, and validated the findings by Sanger sequencing. TP53 mutations were identified and validated in 6 (2·6%) patients that impacted the DNA‐binding domain. All six were MYD88‐ and CXCR4‐mutated. Ibrutinib showed activity in patients carrying all three mutations. With a median follow‐up of 18 months, 2 (33%) with biallelic TP53 inactivation died of progressive disease. TP53 mutations are rare in WM, and associate with MYD88 and CXCR4 mutations. WM patients with TP53 mutations show response to ibrutinib. [ABSTRACT FROM AUTHOR]

The article discusses the myddosome assembly in the disease called Waldenstrom macroglobulinaemia (WM). Also cited are the MYD88 mutations as expressed in WM, immune-privileged lymphomas, activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), marginal zone lymphoma, and chronic lymphocytic leukaemia (CLL), the composition of MYD88 protein, and MYD88 dimerization.

The article reports on the response to ibrutinib therapy of a 59-year-old male patient of Waldenström macroglobulinemia (WM) with Bing Neel syndrome (BNS) whose central nervous system (CNS) disease progressed despite multiple regimens. Topics covered include patient history, information on ibrutinib as a Bruton Tyrosine Kinase (BTK) inhibitor and CNS penetration of ibrutinib.

CXCR4 WHIM frameshift and nonsense mutations follow MYD88L265P as the most common somatic variants in Waldenström Macroglobulinaemia ( WM), and impact clinical presentation and ibrutinib response. While the nonsense ( CXCR4S338X) mutation has been investigated, little is known about CXCR4 frameshift ( CXCR4FS) mutations. We engineered WM cells to express CXCR4FS mutations present in patients, and compared their CXCL12 ( SDF-1a) induced signalling and ibrutinib sensitivity to CXCR4wild-type (WT) and CXCR4S338X cells. Following CXCL12 stimulation, CXCR4FS and CXCR4S338X WM cells showed impaired CXCR4 receptor internalization, and enhanced AKT1 (also termed AKT) and MAPK1 (also termed ERK) activation versus CXCRWT cells ( P < 0·05), though MAPK1 activation was more prolonged in CXCR4S338X cells ( P < 0·05). CXCR4FS and CXCR4S338X cells, but not CXCR4WT cells, were rescued from ibrutinib-triggered apoptosis by CXCL12 that was reversed by AKT1, MAPK1 or CXCR4 antagonists. Treatment with an inhibitor that blocks MYD88L265P signalling triggered similar levels of apoptosis that was not abrogated by CXCL12 treatment in CXCR4WT and CXCR4WHIM cells. These studies show a functional role for CXCR4FS mutations in WM, and provide a framework for the investigation of CXCR4 antagonists with ibrutinib in CXCR4WHIM-mutated WM patients. Direct inhibition of MYD88L265P signalling overcomes CXCL12 triggered survival effects in CXCR4WHIM-mutated cells supporting a primary role for this survival pathway in WM. [ABSTRACT FROM AUTHOR]

The article focuses on a study regarding the role of B-cell selection in determination of the MYD88 mutation status in waldenstrom macroglobulinemia (WM). It mentions that WM is characterized by bone marrow (BM) with lymphoplasmacytic lymphoma and helps in the production of a monoclonal immunoglobulin (Ig) M protein. It also mentions the importance of MYD88 mutational status in diagnostic, prognostic and treatment of WM patients.