Center for Molecular Medicine Cologne

Martin Peifer / H Christian Reinhardt - A 9

Exploring actionable cooperating lesions that drive Myd88-mediated lymphomagenesis

Oncogenic MYD88mutations occur in 39% of all human activated B cell-type diffuse large B cell lymphomaS (ABC-DLBCL). Data from patients and our mouse models of Myd88-driven ABC-DLBCL indicate that Myd88mutations cooperate with additional genomic aberrations in ABC-DLBCL lymphomagenesis. MYD88 is a difficult drug target. Thus, we propose to search for druggable mutations that cooperate with MYD88in ABC-DLBCL lymphomagenesis. In addition, we propose a candidate approach for targeting MYD88-driven ABC-DLBCL in vivo, using IRAK4 inhibitors. 

Introduction

The recent large-scale exploration and character-ization of the genetic landscape in DLBCL may provide ample opportunity to conceive potential routes for tumor genome-stratified targeted thera-peutic interventions. Particularly in ABC-DLBCL, a number of potential intervention strategies, targe-ting BTK, IRAK4, PI3Kdand others alone or in com-bination, have recently been reported primarily in cell lines and xenograft transplantation models [1-5]. Probably the most advanced data for targeted therapeutic intervention in ABC-DLBCL exist for the BTK inhibitor ibrutinib, which was recently shown to display remarkable single agent activity in relapsed/ refractory ABC-DLBCL carrying mutations in both MYD88and CD79Bin the context of an open-label, non-randomized, prospective analysis [2]. There is also emerging clinical data for the BCL2 inhibitor venetoclax, which achieved an overall response rate of 18% in relapsed/refractory DLBCL in the context of a phase I trial [6]. Lastly, immune checkpoint blockade is emerging as a potential route for thera-peutic intervention in relapsed/refracttory DLBCL [7]. For instance, the anti-PD1 monoclonal antibody nivolumab achieved an overall response rate of 36% in DLBCL patients in a phase I, open-label, dose-escalation, cohort-ex-pansion study [8]. However, it remains somewhat unclear which pa-tients truly benefit from venetoclax or nivolumab. Thus, reli-able biomarkers or genetic predictors are critical to define the most sensitive patient population.

Results and discussion

Here, we characterized a mouse model of Myd88and BCL2-driven DLBCL. In essence, we show that Myd88 p.L252P and BCL2 cooperate in DLBCL lym-phomagenesis. The resulting lymphomas display gene expression profiles that are strikingly similar to human ABC-DLBCL. Moreover, in addition to the engineered aberrations in Myd88and BCL2, these lymphomas also spontaneously acquire single nuc-leotide variants that are also detectable in human DLBCL, including mutations in Pim1MycPou2f2Nfkbiaand Kmt2d. We also assessed the effects of Myd88 p.L252P expression in non-transformed B cells. We specifi-cally analyzed spontaneous, MYD88-centered protein complex formation in naïve B cells and found significantly more complexesinvolving MYD88 together with IRAK1, IRAK4, IgM and BTK, compared to wt controls. These ex vivo experiments suggest that MYD88p.L252Pconstitutively nucleates a signaling complex, physically linking BCR and TLR signaling molecules in non-transformed B cells. These data are in line with the recently reported presence of the so-called My-T-BCR complex in ABC-DLBCL lymphoma cell lines [9].Moreover, these data are supported by a report, indicating that BTK localizes in a protein complex with MYD88 in p.L265P-expressing OCI-Ly3 DLBCL cells [10]. Further investigation into the impact of Myd88 p.L252P expression in non-transformed B cells revealed the presence of auto-reactive antibodies in MC, BC and MBC animals. Particularly the robust detection of auto-reactive antibodies in MC animals was surprising, as it suggests that B cell-specific expression of Myd88 p.L252P is tolerated in vivo. This observation is in contrast to the results of a recently reported transplantation experiment, where mature B cells were first transduced with MYD88 p.L265P and subsequently transplanted into Rag1-/-recipients [11]. In these experiments, MYD88p.L265P was sufficient to initiate a spontan-eous proliferation burst in mature B cells in vitroand in vivo [11]. Nevertheless, the MYD88p.L265P-induced aberrant clonal growth was rapidly limited in a Bim-dependent manner [11]. However, it is important to note that an overexpression system was used in those experiments, while we employ Myd88ex-pression from its endogenous locus in vivo. Moreover, as we use Cd19Creto mediate recombination, the entire B cell pool in our experimental system carries the Myd88 p.L252P mutation. Thus, B cell competition effects are very limited in our mouse model. We also employed our MBC model as a preclinical tool, which mimics central features of ABC-DLBCL (surface marker profile, expression profile, driver mutations and spontaneously developing muta-tional profile). Particularly the analysis of murine and human tissue specimens and transcription profiles revealed that ABC-DLBCL cases display higher CD274(encoding PD-L1) levels, than GCB-DLBCL cases. There is further substantial evidence that mechanistically supports the high PD-L1 expression levels in our MBC model: IFN-gand Myd88-dependent TLR signaling was recently shown to drive PD-L1 expression in multiple myeloma cells [12]. Intriguingly, we found signify-cantly higher IFN-glevels in the serum of MBC mice, compared to animals carrying Myc-driven lym-phomas. Moreover, RNA-Seq data analysis of 1001 human DLBCL cases revealed that a sizeable fraction of human DLBCL cases (13%) harbors high BCL2and CD274expression levels. To particularly target this population, we assessed the preclinical efficacy of combined BCL2- and PD1 blockade. While both single agents displayed mild activity in the MBC model, combined venetoclax and RMP1-14 led to significantly increased overall survival, com-pared to the single agents or vehicle. These observations provide further evidence for the clinical develop-ment of BCL2 and PD1/PD-L1 inhibitors in the clinical arena. In this context, it is important to reiterate that single agent venetoclax was recently shown to achieve an ORR of 18% in relapsed/re-fractory DLBCL [6]. Similarly, single agent nivolumab achieved an ORR of 36% in DLBCL [8]. Our data now indicate that DLBCL patients displaying high-level PD-L1 and BCL2 exist and that these patients may be particularly well-suited to receive combined BCL2- and PD1 blockade. This strategy may be parti-cularly useful in relapsed/re-fractory ABC-DLBCL, or those patients that are not eligible for intensive consolidation regimens, involving autologous stem cell support. Altogether, we provide a detailed molecular analysis of the MBC model, including the comparison with Myc-driven lymphomas and a large series of human DLBCL cases. These experi-ments indicate that the MBC model reflects key aspects of human ABC-DLBCL. Moreover, we em-ploy the MBC model to derive a combination stra-tegy involving PD1-and BCL2 blockade for the treatment of MYD88- and BCL2-altered aggressive lymphomas.

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    Schmitt A, Knittel G, Welcker D, Yang TP, George J, Nowak M, Leeser U, Buttner R, Perner S, Peifer M, and Reinhardt HC (2017). ATM Deficiency Is Associated with Sensitivity to PARP1- and ATR Inhibitors in Lung Adenocarcinoma. Cancer Res 77, 3040-56.

    Weischenfeldt J, Dubash T, Drainas AP, Mardin BR, Chen Y, Stutz AM, Waszak SM, Bosco G, Halvorsen AR, Raeder B, Efthymiopoulos T, Erkek S, Siegl C, Brenner H, Brustugun OT, Dieter SM, Northcott PA, Petersen I, Pfister SM, Schneider M, Solberg SK, Thunissen E, Weichert W, Zichner T, Thomas R, Peifer M, Helland A, Ball CR, Jechlinger M, Sotillo R, Glimm H, and Korbel JO (2017). Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking. Nat Genet 49, 65-74.

    Prof. Dr. Martin Peifer CMMC Cologne
    Prof. Dr. Martin Peifer

    Dept. of Translational Genomics / RG location - CMMC Building

    Principal Investigator A 9 / CAP 6

    +49 221 478 96863

    +49 221 478 97902

    Dept. of Translational Genomics / RG location - CMMC Building

    Robert-Koch-Str. 21

    50931 Cologne

    https://www.cds.uni-koeln.de/13520.html

    CMMC Profile Page

    Publications - Martin Peifer

    Link to PubMed

    Affiliations

    KFO 286

    CDS

    Prof. Dr. H Christian Reinhardt CMMC Cologne
    Prof. Dr. H Christian Reinhardt

    Dept. I of Internal Medicine / RG location - Dept. of Translational Genomics

    Co-Principal Investigator A 9

    Executive Board Member

    +49 221 478 96701

    +49 221 478 97835

    Dept. I of Internal Medicine / RG location - Dept. of Translational Genomics

    Weyertal 115 b

    50931 Cologne

    http://reinhardt.cecad-labs.uni-koeln.de/Lab-Members.637.0.html

    CMMC Profile Page

    Curriculum Vitae (CV)

    Publications - H Christian Reinhardt

    Link to PubMed

    Affiliations

    KFO 286

    Group Members

    Gero Knittel (Senior Scientist), PhD (PostDoc)
    Ruth Flümann, MD (PostDoc)