CD79B and MYD88 mutations in diffuse large B-cell lymphoma

Kim, Yuil; Ju, Hyunjeong; Kim, Dong Hoon; Yoo, Hae Young; Kim, Suk Jin; Kim, Won Seog; Ko, Young Hyeh

doi:10.1016/j.humpath.2013.10.023

Cited by 46 publications

(55 citation statements)

References 28 publications

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“…In primary DLBCL of the CNS or testis, the cell cycle regulator PIM1 and the regulators ( MYD88 and CD79B ) of NF-κB pathway were the most frequently mutated genes, which are consistent with the recent data of Bruno et al [24]. The prevalence of MYD88 mutation in primary DLBCL of the CNS or testis was significantly higher than previously reported studies in the whole DLBCL series ranging from 6.5% to 19.3% but similar to the observation in ABC-DLBCL (39%) [13, 18, 25–27]. MYD88 has also been recurrently found mutated in majority of lymphoplasmacytic lymphoma (> 90%) [28, 29].…”

Section: Discussionsupporting

confidence: 90%

Mutations or copy number losses of CD58 and TP53 genes in diffuse large B cell lymphoma are independent unfavorable prognostic factors

et al. 2016

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The advent of next generation sequencing (NGS) technologies has expedited the discovery of novel genetic lesions in DLBCL. The prognostic significance of these identified gene mutations is largely unknown. In this study, we performed NGS for the 27 genes most frequently implicated in 196 patients. Interestingly, TP53 mutations were found to be significantly more common in DLBCL with MYC translocations (r = 0.446, P = 0.034). While no gene mutation was found to be more prevalent in patients with DLBCL with bone marrow involvement, MYD88 mutations were more common in primary DLBCL of the CNS or testis. To evaluate the prognostic significance of the abnormalities of these 27 genes, a total of 165 patients with newly diagnosed DLBCL, NOS were included in a multivariate survival analysis. Surprisingly, in addition to the TP53 mutation, CD58 mutation was found to predict poor clinical outcome. Furthermore, copy number loss of CD58 or TP53 was also identified to be an independent negative prognostic factor. Our results have uncovered the previously unknown critical impact of gene mutations on the prognosis of DLBCL and are fundamentally important for the future design of tailored therapy for improved clinical outcomes.

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Section: Discussionsupporting

confidence: 90%

Mutations or copy number losses of CD58 and TP53 genes in diffuse large B cell lymphoma are independent unfavorable prognostic factors

et al. 2016

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“…3), so the meta-analysis was performed again except for Kim et al . 18 study. This pooling analysis showed that DLBCL patients with the MYD88 L265P mutation had low overall survival rates (HR = 3.244; 95% CI: 1.784–5.826; p < 0.001, Q = 0.068, I 2 = 0.000) (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 95%

Clinicopathologic significance of MYD88 L265P mutation in diffuse large B-cell lymphoma: a meta-analysis

Lee

Jeong

Choi

et al. 2017

Sci Rep

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The precise clinicopathologic significance of myeloid differentiation primary response gene (MYD88) L265P mutation in diffuse large B-cell lymphomas (DLBCLs) remains elusive. To investigate the frequency and clinicopathologic significance of the MYD88 L265P mutation in DLBCLs, we conducted a meta-analysis of 40 published studies on 2736 DLBCL patients. We collected relevant published research findings identified using the PubMed and Embase databases. The effect sizes of outcome parameters were calculated using a random-effects model. In this meta-analysis, the MYD88 L265P mutation in DLBCL showed a significant difference according to tumor sites. The overall incidence of the MYD88 L265P mutation in DLBCLs, excluding the central nervous system and testicular DLBCLs, was 16.5%. Notably, the MYD88 L265P mutation rates of CNS and testicular DLBCL patients were 60% and 77%, respectively. Interestingly, the MYD88 L265P mutation was more frequently detected in activated B-cell-like (ABC) or non-germinal center B-cell-like (GCB) than GCB subtype (OR = 3.414, p < 0.001). The MYD88 L265P mutation was significantly associated with old age and poor overall survival, but not with sex and clinical stage. This pooled analysis demonstrates that the MYD88 L265P mutation is significantly associated with the tumor sites and molecular subtypes in DLBCL patients.Myeloid differentiation primary response gene (MYD88) is an adaptor protein that activates the nuclear transcription factor κB (NF-κB) signaling through most of the Toll-like receptors (TLRs) 1 . An L265P mutation, a change from leucine (CTC) to proline (CCG), in the MYD88 Toll/interleukin (IL)-1 receptor domain, recruits MYD88 protien to the cytoplasmic tail of TLRs to form an active complex. The complex promotes NF-κB and Janus kinase-signal transducer and activator of transcription 3 (JAK-STAT3) signaling 1 .Recently, many investigators have reported that the prevalence of MYD88 L265P mutation ranges from 0% to 94% in different series of diffuse large B-cell lymphoma (DLBCL) patients 2-41 . However, since the MYD88 L265P mutation occurs at various frequencies of DLBCL, a general consensus on clinicopathologic implications has not been reached. DLBCL is a heterogeneous non-Hodgkin's lymphoma mainly comprising molecular subtypes such as germinal center B-cell-like (GCB) and activated B-cell-like (ABC) types 42 . Several studies have suggested that the frequency of MYD88 L265P mutation may vary depending on the tumor site or molecular subtype of DLBCL 2,8,21,24,30,41 , but individual studies with different designs hinder clear conclusions. Furthermore, the clinicopathologic significance of the MYD88 L265P mutation in each DLBCL patient was controversial.To address these controversies, we conducted a meta-analysis to examine the frequency of MYD88 L265P mutation and the relationship between this mutation and the clinicopathologic parameters of DLBCL patients. ResultsPrevalence of MYD88 L265P mutation in diffuse large B-cell lymphoma. On pooled analysis of 40 studies, includin...

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“…Confirming previously published data, we found a substantial overrepresentation of MYD88 and CD79B mutations in ABC-DLBCLs compared with GCB-DLBCLs (Figure 3A,C; supplemental Table 1). 9,20,21 Furthermore, the anti-apoptotic oncogene BCL2 is frequently deregulated in human DLBCL. 22,23 Whereas the chromosomal translocation t(14;18)(q32;q21), which juxtaposes BCL2 and the IGHV enhancer, is commonly observed in GCB-DLBCL, 23 focal copy number gains are more commonly observed in ABC-DLBCL (;30% to 40%).…”

Section: Resultsmentioning

confidence: 99%

B-cell–specific conditional expression of Myd88p.L252P leads to the development of diffuse large B-cell lymphoma in mice

Knittel

Liedgens

Korovkina

et al. 2016

Blood

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Key Points• B-cell-specific expression of Myd88 p.L252P leads to the development of DLBCL in mice.• The Myd88 p.L252P mutation cooperates with BCL2 amplifications in ABC-DLBCL lymphomagenesis in vivo.The adaptor protein MYD88 is critical for relaying activation of Toll-like receptor signaling to NF-kB activation. MYD88 mutations, particularly the p.L265P mutation, have been described in numerous distinct B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL). Twenty-nine percent of activated B-cell-type DLBCL (ABC-DLBCL), which is characterized by constitutive activation of the NF-kB pathway, carry the p.L265P mutation. In addition, ABC-DLBCL frequently displays focal copy number gains affecting BCL2. Here, we generated a novel mouse model in which Cre-mediated recombination, specifically in B cells, leads to the conditional expression of Myd88 p.L252P (the orthologous position of the human MYD88 p.L265P mutation) from the endogenous locus.These mice develop a lymphoproliferative disease and occasional transformation into clonal lymphomas. The clonal disease displays the morphologic and immunophenotypical characteristics of ABC-DLBCL. Lymphomagenesis can be accelerated by crossing in a further novel allele, which mediates conditional overexpression of BCL2. Cross-validation experiments in human DLBCL samples revealed that both MYD88 and CD79B mutations are substantially enriched in ABC-DLBCL compared with germinal center B-cell DLBCL. Furthermore, analyses of human DLBCL genome sequencing data confirmed that BCL2 amplifications frequently cooccurred with MYD88 mutations, further validating our approach. Finally, in silico experiments revealed that MYD88-mutant ABC-DLBCL cells in particular display an actionable addiction to BCL2. Altogether, we generated a novel autochthonous mouse model of ABC-DLBCL that could be used as a preclinical platform for the development and validation of novel therapeutic approaches for the treatment of ABC-DLBCL. (Blood. 2016;127(22):2732-2741

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CD79B and MYD88 mutations in diffuse large B-cell lymphoma

Cited by 46 publications

References 28 publications

Mutations or copy number losses of CD58 and TP53 genes in diffuse large B cell lymphoma are independent unfavorable prognostic factors

Mutations or copy number losses of CD58 and TP53 genes in diffuse large B cell lymphoma are independent unfavorable prognostic factors

Clinicopathologic significance of MYD88 L265P mutation in diffuse large B-cell lymphoma: a meta-analysis

B-cell–specific conditional expression of Myd88p.L252P leads to the development of diffuse large B-cell lymphoma in mice

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