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An Autochthonous Mouse Model of Myd88- and BCL2-Driven Diffuse Large B-cell Lymphoma Reveals Actionable Molecular Vulnerabilities.

ABSTRACT: Based on gene expression profiles, diffuse large B cell lymphoma (DLBCL) is sub-divided into germinal center B cell-like (GCB) and activated B cell-like (ABC) DLBCL. Two of the most common genomic aberrations in ABC-DLBCL are mutations in MYD88, as well as BCL2 copy number gains. Here, we employ immune phenotyping, RNA-Seq and whole exome sequencing to characterize a Myd88 and Bcl2-driven mouse model of ABC-DLBCL. We show that this model resembles features of human ABC-DLBCL. We further demonstrate an actionable dependence of our murine ABC-DLBCL model on BCL2. This BCL2 dependence was also detectable in human ABC-DLBCL cell lines. Moreover, human ABC-DLBCLs displayed increased PD-L1 expression, compared to GCB-DLBCL. In vivo experiments in our ABC-DLBCL model showed that combined venetoclax and RMP1-14 significantly increased the overall survival of lymphoma bearing animals, indicating that this combination may be a viable option for selected human ABC-DLBCL cases harboring MYD88 and BCL2 aberrations.

SUBMITTER: Flumann R

PROVIDER: S-EPMC7806186 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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An Autochthonous Mouse Model of Myd88- and BCL2-Driven Diffuse Large B-cell Lymphoma Reveals Actionable Molecular Vulnerabilities.

Flümann Ruth R Rehkämper Tim T Nieper Pascal P Pfeiffer Pauline P Holzem Alessandra A Klein Sebastian S Bhatia Sanil S Kochanek Moritz M Kisis Ilmars I Pelzer Benedikt W BW Ahlert Heinz H Hauer Julia J da Palma Guerreiro Alexandra A Ryan Jeremy A JA Reimann Maurice M Riabinska Arina A Wiederstein Janica J Krüger Marcus M Deckert Martina M Altmüller Janine J Klatt Andreas R AR Frenzel Lukas P LP Pasqualucci Laura L Béguelin Wendy W Melnick Ari M AM Sander Sandrine S Montesinos-Rongen Manuel M Brunn Anna A Lohneis Philipp P Büttner Reinhard R Kashkar Hamid H Borkhardt Arndt A Letai Anthony A Persigehl Thorsten T Peifer Martin M Schmitt Clemens A CA Reinhardt Hans Christian HC Knittel Gero G

Blood cancer discovery 20210101 1

Based on gene expression profiles, diffuse large B cell lymphoma (DLBCL) is sub-divided into germinal center B cell-like (GCB) and activated B cell-like (ABC) DLBCL. Two of the most common genomic aberrations in ABC-DLBCL are mutations in MYD88, as well as BCL2 copy number gains. Here, we employ immune phenotyping, RNA-Seq and whole exome sequencing to characterize a Myd88 and Bcl2-driven mouse model of ABC-DLBCL. We show that this model resembles features of human AB ...[more]

PMID: 33447829

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Project description:Diffuse large B‑cell lymphoma (DLBCL), the most common type of non‑Hodgkin's 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.

Dataset Information

An Autochthonous Mouse Model of Myd88- and BCL2-Driven Diffuse Large B-cell Lymphoma Reveals Actionable Molecular Vulnerabilities.

Publications

An Autochthonous Mouse Model of Myd88- and BCL2-Driven Diffuse Large B-cell Lymphoma Reveals Actionable Molecular Vulnerabilities.

Similar Datasets

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