Oncogenic MYD88 mutations in lymphoma: novel insights and therapeutic possibilities

Weber, Alexander N.R.; Gloria, Yamel Cardona; Çınar, Özcan; Reinhardt, Hans Christian; Pezzutto, Antonio; Wolz, Olaf‐Oliver

doi:10.1007/s00262-018-2242-9

Cited by 29 publications

(27 citation statements)

References 64 publications

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“…Schmitz et al (25) found four dlBcl genotype subtypes, namely, Mcd (based on the co-occurrence of MYd88, l265P and cd79B mutations), Bn2 (based on Bcl6 fusions and noTcH2 mutations), n1 (based on noTcH1 mutations) and eZB (based on eZH2 mutations and Bcl2 translocations), and poorer prognosis rates in patients with Mcd and n1 subtypes. Weber et al (26) proposed immunotherapy for MYd88 l265P mutant tumors. it has been hypothesized that dlBcl could be treated with MYD88 L265P peptide as a novel tumor-specific antigen to induce cytotoxic T cell reaction (26).…”

Section: Introductionmentioning

confidence: 99%

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Prognostic value of MYD88 L265P mutation in diffuse large B cell lymphoma via droplet digital PCR

Niu

Nuerlan

et al. 2020

Mol Med Rep

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To assess the prevalence and prognostic value of myeloid differentiation factor 88 (MYd88) expression and mutational status in diffuse large B cell lymphoma (dlBcl), a total cohort of 100 patients with dlBcl were studied using immunohistochemistry (iHc) and droplet digital polymerase chain reaction (ddPcr), and the association between MYd88 expression and clinicopathological parameters was analyzed. overall, the positive expression rate of MYd88 protein was 38% and the gene mutation rate was 29%. The positive expression and mutation rates were the highest in the primary central nervous system lymphomas (58.33 and 66.67%, respectively). The coincidence rate of the results of MYd88 expression between iHc and ddPcr results was 73% (73/100). univariate survival analysis showed that age (≥60 years old), high neutrophil/lymphocyte count ratio, low lymphocyte count, c-Myc ≥40%, positive MYd88 protein expression, and gene mutation were associated with poorer prognosis rates. Multivariate survival analysis revealed that MYd88 expression was an independent prognostic factor affecting overall survival. in conclusion, the results of this study demonstrated that MYd88 mutation was a valuable index to evaluate the prognosis of dlBcl. ddPcr can be used as a method for detecting MYd88 mutations, although it was not completely consistent with the results of iHc.

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Section: Introductionmentioning

confidence: 99%

“…Weber et al (26) proposed immunotherapy for MYd88 l265P mutant tumors. it has been hypothesized that dlBcl could be treated with MYD88 L265P peptide as a novel tumor-specific antigen to induce cytotoxic T cell reaction (26). Hence, developing therapeutic agents for this mutation is becoming increasingly important.…”

Section: Introductionmentioning

confidence: 99%

Prognostic value of MYD88 L265P mutation in diffuse large B cell lymphoma via droplet digital PCR

Niu

Nuerlan

et al. 2020

Mol Med Rep

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“…MYD88 L265P was identified as an oncogenic driver mutation, with enhanced phosphorylation of IRAK kinases and activation of the NF-κB and JAK-STAT3 signaling pathways, resulting in the promotion of cell survival in numerous B-cell neoplasms, including ABC DLBCL (8,12,28). Furthermore, mice occasionally developed ABC-DLBCL-like clonal lymphomas following conditional expression of MYD88 L265P in B cells specifically (29,30).…”

Section: Discussionmentioning

confidence: 99%

Disrupting myddosome assembly in diffuse large B‑cell lymphoma cells using the MYD88 dimerization inhibitor ST2825

et al. 2019

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Diffuse large B-cell lymphoma (DLBCL), the most common type of non-Hodgkins lymphoma, is classified into germinal center and activated B cell (ABC) subtypes. The myeloid differentiation primary response gene 88 (MYD88) L265P mutation is the most prevalent oncogenic mutation among patients with ABC DLBCL, the subtype that has the more inferior outcome. MYD88 oligomerization driven by the L265P mutant augments myddosome assembly and triggers the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, highlighting MYD88 oligomerization as a potential therapeutic target for this malignancy. The synthetic peptidomimetic compound ST2825, which has previously been used as an anti-inflammatory agent, has been reported to inhibit MYD88 dimerization. In the present study, the anticancer effects of ST2825 were investigated using L265P-expressing ABC DLBCL cell lines. Using confocal microscopy and high-molecular-weight fraction experiments, it was revealed that L265P-associated myddosome assembly was disrupted by ST2825. The results also revealed that disrupting myddosome assembly promoted the death of ABC DLBCL cells harboring the L265P mutation, as well as downregulating survival signals, including the inhibition of NF-κB and the suppression of IL-10 and interferon-β production. Further co-immunoprecipitation studies demonstrated that MYD88 bound to BTK in L265P-DLBCL cells, and that this binding was abrogated following ST2825 treatment. Furthermore, the combination of myddosome-assembly disruption and BTK or BCL-2 signaling inhibition led to synergistic ABC DLBCL cell death, and more robust inhibition of NF-κB activity or increased apoptosis, respectively. The results of the present study provide evidence that the synthetic peptidomimetic compound ST2825, which targets myddosome assembly, may serve as a pharmacological inhibitor. ST2825 has the potential for clinical use in patients with L265P DLBCL, and other B-cell neoplasms driven by activated MYD88 signaling.

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“…The oncogenic activity of MYD88(L265P), as well as its high frequency in several B-NHL subtypes, ensure that MYD88 and its affiliated signaling pathways are very interesting for targeted therapeutic strategies. As reviewed by Yu et al 18 and Weber et al, 119 several targets are conceivable for direct or indirect inhibition, such as IRAK1 and IRAK4 in the myddosome-complex, TAK1 in downstream signaling, BTK in the BCR pathway, TLR9 in the My-T-BCR supercomplex, and components of the concurrently activated PI3K/AKT/mTOR and HCK pathways ( Figure 2).…”

Section: Targeted Therapiesmentioning

confidence: 99%

“…An alternative therapeutic approach for these patients, as reviewed by Weber et al, 119 is the induction of a T-cell mediated immune response towards tumor-specific neoepitopes that are derived from MYD88(L265P). In in vitro experiments, such neoepitopes, presented by major histocompatibility class I molecules, prompted a cytotoxic CD8 + T-cell response.…”

Section: Targeted Therapiesmentioning

confidence: 99%

MYD88 in the driver’s seat of B-cell lymphomagenesis: from molecular mechanisms to clinical implications

et al. 2019

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Oncogenic MYD88 mutations in lymphoma: novel insights and therapeutic possibilities

Cited by 29 publications

References 64 publications

Prognostic value of MYD88 L265P mutation in diffuse large B cell lymphoma via droplet digital PCR

Prognostic value of MYD88 L265P mutation in diffuse large B cell lymphoma via droplet digital PCR

Disrupting myddosome assembly in diffuse large B‑cell lymphoma cells using the MYD88 dimerization inhibitor ST2825

MYD88 in the driver’s seat of B-cell lymphomagenesis: from molecular mechanisms to clinical implications

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