Dataset Information

Loss of TNFAIP3 enhances MYD88_L265P-driven signaling in non-Hodgkin lymphoma.

ABSTRACT: MYD88 mutations are one of the most recurrent mutations in hematologic malignancies. However, recent mouse models suggest that MYD88_L265P alone may not be sufficient to induce tumor formation. Interplay between MYD88_L265P and other genetic events is further supported by the fact that TNFAIP3 (A20) inactivation often accompanies MYD88_L265P. However, we are still lacking information about the consequence of MYD88_L265P in combination with TNFAIP3 loss in human B cell lymphoma. Review of our genetic data on diffuse large B cell lymphoma (DLBCL) and Waldenstrom macroglobulinemia (WM), found that a large percentage of DLBCL and WM cases that have a MYD88 mutation also harbor a TNFAIP3 loss, 55% DLBCL and 28% of WM, respectively. To mimic this combination of genetic events, we used genomic editing technology to knock out TNFAIP3 in MYD88_L265P non-Hodgkin's lymphoma (NHL) cell lines. Loss of A20 expression resulted in increased NF-?B and p38 activity leading to upregulation of the NF-?B target genes BCL2 and MYC. Furthermore, we detected the increased production of IL-6 and CXCL10 which led to an upregulation of the JAK/STAT pathway. Overall, these results suggest that MYD88_L265P signaling can be enhanced by a second genetic alteration in TNFAIP3 and highlights a potential opportunity for therapeutic targeting.

SUBMITTER: Wenzl K

PROVIDER: S-EPMC6177394 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Loss of TNFAIP3 enhances MYD88L265P-driven signaling in non-Hodgkin lymphoma.

Wenzl Kerstin K Manske Michelle K MK Sarangi Vivekananda V Asmann Yan W YW Greipp Patricia T PT Schoon Hanna R HR Braggio Esteban E Maurer Matthew J MJ Feldman Andrew L AL Witzig Thomas E TE Slager Susan L SL Ansell Stephen M SM Cerhan James R JR Novak Anne J AJ

Blood cancer journal 20181009 10

MYD88 mutations are one of the most recurrent mutations in hematologic malignancies. However, recent mouse models suggest that MYD88L265P alone may not be sufficient to induce tumor formation. Interplay between MYD88L265P and other genetic events is further supported by the fact that TNFAIP3 (A20) inactivation often accompanies MYD88L265P. However, we are still lacking information about the consequence of MYD88L265P in combination with TNFAIP3 loss in ...[more]

PMID: 30301877

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Project description:BackgroundAutoimmune disorders, including Systemic Lupus Erythematosus (SLE), are associated with increased incidence of hematological malignancies. The matricellular protein osteopontin (OPN) has been linked to SLE pathogenesis, as SLE patients show increased serum levels of OPN and often polymorphisms in its gene. Although widely studied for its pro-tumorigenic role in different solid tumours, the role of OPN in autoimmunity-driven lymphomagenesis has not been investigated yet.MethodsTo test the role of OPN in the SLE-associated lymphomagenesis, the SLE-like prone Faslpr/lpr mutation was transferred onto an OPN-deficient background. Spleen from Faslpr/lpr and OPN-/-Faslpr/lpr mice, as well as purified B cells, were analysed by histopathology, flow cytometry, Western Blot, immunohistochemistry, immunofluorescence and gene expression profile to define lymphoma characteristics and investigate the molecular mechanisms behind the observed phenotype. OPN cellular localization in primary splenic B cells and mouse and human DLBCL cell lines was assessed by confocal microscopy. Finally, gain of function experiments, by stable over-expression of the secreted (sOPN) and intracellular OPN (iOPN) in OPN-/-Faslpr/lpr -derived DLBCL cell lines, were performed for further validation experiments.ResultsDespite reduced autoimmunity signs, OPN-/-Faslpr/lpr mice developed splenic lymphomas with higher incidence than Faslpr/lpr counterparts. In situ and ex vivo analysis featured such tumours as activated type of diffuse large B cell lymphoma (ABC-DLBCL), expressing BCL2 and c-MYC, but not BCL6, with activated STAT3 signaling. OPN-/-Faslpr/lpr B lymphocytes showed an enhanced TLR9-MYD88 signaling pathway, either at baseline or after stimulation with CpG oligonucleotides, which mimic dsDNA circulating in autoimmune conditions. B cells from Faslpr/lpr mice were found to express the intracellular form of OPN. Accordingly, gene transfer-mediated re-expression of iOPN, but not of its secreted isoform, into ABC-DLBCL cell lines established from OPN-/-Faslpr/lpr mice, prevented CpG-mediated activation of STAT3, suggesting that the intracellular form of OPN may represent a brake to TLR9 signaling pathway activation.ConclusionThese data indicate that, in the setting of SLE-like syndrome in which double strand-DNA chronically circulates and activates TLRs, B cell intracellular OPN exerts a protective role in autoimmunity-driven DLBCL development, mainly acting as a brake in the TLR9-MYD88-STAT3 signaling pathway.

Dataset Information

Loss of TNFAIP3 enhances MYD88_L265P-driven signaling in non-Hodgkin lymphoma.

Publications

Loss of TNFAIP3 enhances MYD88<sub>L265P</sub>-driven signaling in non-Hodgkin lymphoma.

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