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. 


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.


  1. Yang Y, Shaffer AL, 3rd, Emre NC, et al. . Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma. Cancer Cell 2012;21:723-737.
  2. Wilson WH, Young RM, Schmitz R, et al. . Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med 2015;21:922-926.
  3. Scott JS, Degorce SL, Anjum R, et al. . Discovery and Optimization of Pyrrolopyrimidine Inhibitors of Interleukin-1 Receptor Associated Kinase 4 (IRAK4) for the Treatment of Mutant MYD88(L265P) Diffuse Large B-Cell Lymphoma. J Med Chem 2017;60:10071-10091.
  4. Kelly PN, Romero DL, Yang Y, et al. . Selective interleukin-1 receptor-associated kinase 4 inhibitors for the treatment of autoimmune disorders and lymphoid malignancy.J Exp Med 2015;212:2189-2201.
  5. Paul J, Soujon M, Wengner AM, et al. . Simultaneous Inhibition of PI3Kdelta and PI3Kalpha Induces ABC-DLBCL Regression by Blocking BCR-Dependent and -Independent Activation of NF-kappaB and AKT. Cancer Cell 2017;31:64-78.
  6. Davids MS, Roberts AW, Seymour JF, et al. . Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma. J Clin Oncol 2017;35:826-833.
  7. Juarez-Salcedo LM, Sandoval-Sus J, Sokol L, Chavez JC, Dalia S. The role of anti-PD-1 and anti-PD-L1 agents in the treatment of diffuse large B-cell lymphoma: The future is now. Crit Rev Oncol Hematol 2017;113:52-62.
  8. Lesokhin AM, Ansell SM, Armand P, et al. . Nivolumab in Patients With Relapsed or Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib Study. J Clin Oncol 2016;34:2698-2704.
  9. Phelan JD, Young RM, Webster DE, et al. . A multiprotein supercomplex controlling oncogenic signalling in lymphoma. Nature 2018;560:387-391.
  10. Yang G, Zhou Y, Liu X, et al. . A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenstrom macroglobulinemia. Blood 2013;122:1222-1232.
  11. Wang JQ, Jeelall YS, Beutler B, Horikawa K, Goodnow CC. Consequences of the recurrent MYD88(L265P) somatic mutation for B cell tolerance. J Exp Med 2014;211:413-426.
  12. Liu J, Hamrouni A, Wolowiec D, et al. . Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression after stimulation with IFN-{gamma} and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway. Blood 2007;110:296-304.
    • Kreuzer KA, ..., Reinhardt HC, ..., Hallek M: The Impact of Complex Karyotype on the Overall Survival of Patients with Relapsed Chronic Lymphocytic Leukemia Treated with Idelalisib Plus Rituximab. Leukemiaaccepted for publication
    • Jachimowicz RD, ...,Peifer M,..., Reinhardt HC*,#, Wieczorek D*, Shiloh Y*: UBQLN4 represses homologous recombination and is overexpressed in aggressive tumors, Cell, 2018 Dec 21. * Shared last authors, #lead author contact
    • Torgovnick A, ...,  Reinhardt HC: The Cdkn1aSUPER mouse as a novel tool to study p53-mediated tumor suppression. Cell Reports, 2018 Oct 23;25(4):1027-1039.e6. 
    • Herling CD, ..., Reinhardt HC, ..., Peifer M: Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia. Nature Communications, 2018 Feb 20;9(1):727. 
    • Schrader A, ... , Peifer MReinhardt HC,..., Herling M: Integrated genetic profiles of T-PLL implicate a TCL1/ATM-centered model of aberrant, but actionable damage responses. Nature Communications, 2018 Feb 15;9(1):697. 
    • Knittel G, ..., Peifer M, ..., Reinhardt HC: Two mouse models reveal an actionable PARP1 dependence in aggressive chronic lymphocytic leukemia. Nature Communications, 2017 Jul 28;8(1):153. 

    Castiglione, R., Alidousty, C., Holz, B., Wagener, S., Baar, T., Heydt, C., Binot, E., Zupp, S., Kron, A., Wolf, J., Merkelbach-Bruse, S., Reinhardt, H.C., Buettner, R., and Schultheis, A.M. (2019). Comparison of the genomic background of MET-altered carcinomas of the lung: biological differences and analogies. Mod Pathol 32, 627-38.

    Dammert, M.A., Bragelmann, J., Olsen, R.R., Bohm, S., Monhasery, N., Whitney, C.P., Chalishazar, M.D., Tumbrink, H.L., Guthrie, M.R., Klein, S., Ireland, A.S., Ryan, J., Schmitt, A., Marx, A., Ozretic, L., Castiglione, R., Lorenz, C., Jachimowicz, R.D., Wolf, E., Thomas, R.K., Poirier, J.T., Buttner, R., Sen, T., Byers, L.A., Reinhardt, H.C., Letai, A., Oliver, T.G., and Sos, M.L. (2019). MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer. Nat Commun 10, 3485.

    Frank, S., Ahuja, G., Bartsch, D., Russ, N., Yao, W., Kuo, J.C., Derks, J.P., Akhade, V.S., Kargapolova, Y., Georgomanolis, T., Messling, J.E., Gramm, M., Brant, L., Rehimi, R., Vargas, N.E., Kuroczik, A., Yang, T.P., Sahito, R.G.A., Franzen, J., Hescheler, J., Sachinidis, A., Peifer, M., Rada-Iglesias, A., Kanduri, M., Costa, I.G., Kanduri, C., Papantonis, A., and Kurian, L. (2019). yylncT Defines a Class of Divergently Transcribed lncRNAs and Safeguards the T-mediated Mesodermal Commitment of Human PSCs. Cell Stem Cell 24, 318-27 e8.

    Grimm, C., Fischer, A., Farrelly, A.M., Kalachand, R., Castiglione, R., Wasserburger, E., Hussong, M., Schultheis, A.M., Altmuller, J., Thiele, H., Reinhardt, H.C., Hauschulz, K., Hennessy, B.T., Herwig, R., Lienhard, M., Buettner, R., and Schweiger, M.R. (2019). Combined Targeted Resequencing of Cytosine DNA Methylation and Mutations of DNA Repair Genes with Potential Use for Poly(ADP-Ribose) Polymerase 1 Inhibitor Sensitivity Testing. J Mol Diagn 21, 198-213.

    Jachimowicz, R.D., and Reinhardt, H.C. (2019). UBQLN4 promotes non-homologous end joining by repressing DNA end-resection. Mol Cell Oncol 6, 1575692.

    Jachimowicz, R.D., Beleggia, F., Isensee, J., Velpula, B.B., Goergens, J., Bustos, M.A., Doll, M.A., Shenoy, A., Checa-Rodriguez, C., Wiederstein, J.L., Baranes-Bachar, K., Bartenhagen, C., Hertwig, F., Teper, N., Nishi, T., Schmitt, A., Distelmaier, F., Ludecke, H.J., Albrecht, B., Kruger, M., Schumacher, B., Geiger, T., Hoon, D.S.B., Huertas, P., Fischer, M., Hucho, T., Peifer, M., Ziv, Y., Reinhardt, H.C., Wieczorek, D., and Shiloh, Y. (2019). UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors. Cell 176, 505-19 e22.

    Kreuzer, K.A., Furman, R.R., Stilgenbauer, S., Dubowy, R.L., Kim, Y., Munugalavadla, V., Lilienweiss, E., Reinhardt, H.C., Cramer, P., Eichhorst, B., Hillmen, P., O'Brien, S.M., Pettitt, A.R., and Hallek, M. (2019). The impact of complex karyotype on the overall survival of patients with relapsed chronic lymphocytic leukemia treated with idelalisib plus rituximab. Leukemia10.1038/s41375-019-0533-6.

    Nieroda, L., Maas, L., Thiebes, S., Lang, U., Sunyaev, A., Achter, V., and Peifer, M. (2019). iRODS metadata management for a cancer genome analysis workflow. BMC Bioinformatics 20, 29.

    Ackermann S, Cartolano M, Hero B, Welte A, Kahlert Y, Roderwieser A, Bartenhagen C, Walter E, Gecht J, Kerschke L, Volland R, Menon R, Heuckmann JM, Gartlgruber M, Hartlieb S, Henrich KO, Okonechnikov K, Altmuller J, Nurnberg P, Lefever S, de Wilde B, Sand F, Ikram F, Rosswog C, Fischer J, Theissen J, Hertwig F, Singhi AD, Simon T, Vogel W, Perner S, Krug B, Schmidt M, Rahmann S, Achter V, Lang U, Vokuhl C, Ortmann M, Buttner R, Eggert A, Speleman F, O'Sullivan RJ, Thomas RK, Berthold F, Vandesompele J, Schramm A, Westermann F, Schulte JH, Peifer M, and Fischer M (2018). A mechanistic classification of clinical phenotypes in neuroblastoma. Science 362, 1165-1170.

    Castiglione R, Alidousty C, Holz B, Wagener S, Baar T, Heydt C, Binot E, Zupp S, Kron A, Wolf J, Merkelbach-Bruse S, Reinhardt HC, Buettner R, and Schultheis AM (2018). Comparison of the genomic background of MET-altered carcinomas of the lung: biological differences and analogies. Mod Pathol 10.1038/s41379-018-0182-8.

    Cun Y, Yang TP, Achter V, Lang U, and Peifer M (2018). Copy-number analysis and inference of subclonal populations in cancer genomes using Sclust. Nat Protoc 13, 1488-1501.

    Drapkin BJ, George J, Christensen CL, Mino-Kenudson M, Dries R, Sundaresan T, Phat S, Myers DT, Zhong J, Igo P, Hazar-Rethinam MH, Licausi JA, Gomez-Caraballo M, Kem M, Jani KN, Azimi R, Abedpour N, Menon R, Lakis S, Heist RS, Buttner R, Haas S, Sequist LV, Shaw AT, Wong KK, Hata AN, Toner M, Maheswaran S, Haber DA, Peifer M, Dyson N, Thomas RK, and Farago AF (2018). Genomic and Functional Fidelity of Small Cell Lung Cancer Patient-Derived Xenografts. Cancer Discov 8, 600-615.

    Fassunke J, Muller F, Keul M, Michels S, Dammert MA, Schmitt A, Plenker D, Lategahn J, Heydt C, Bragelmann J, Tumbrink HL, Alber Y, Klein S, Heimsoeth A, Dahmen I, Fischer RN, Scheffler M, Ihle MA, Priesner V, Scheel AH, Wagener S, Kron A, Frank K, Garbert K, Persigehl T, Pusken M, Haneder S, Schaaf B, Rodermann E, Engel-Riedel W, Felip E, Smit EF, Merkelbach-Bruse S, Reinhardt HC, Kast SM, Wolf J, Rauh D, Buttner R, and Sos ML (2018). Overcoming EGFR(G724S)-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors. Nat Commun 9, 4655.

    Frank S, Ahuja G, Bartsch D, Russ N, Yao W, Kuo JC, Derks JP, Akhade VS, Kargapolova Y, Georgomanolis T, Messling JE, Gramm M, Brant L, Rehimi R, Vargas NE, Kuroczik A, Yang TP, Sahito RGA, Franzen J, Hescheler J, Sachinidis A, Peifer M, Rada-Iglesias A, Kanduri M, Costa IG, Kanduri C, Papantonis A, and Kurian L (2018). yylncT Defines a Class of Divergently Transcribed lncRNAs and Safeguards the T-mediated Mesodermal Commitment of Human PSCs. Cell Stem Cell10.1016/j.stem.2018.11.005.

    George J, Walter V, Peifer M, Alexandrov LB, Seidel D, Leenders F, Maas L, Muller C, Dahmen I, Delhomme TM, Ardin M, Leblay N, Byrnes G, Sun R, De Reynies A, McLeer-Florin A, Bosco G, Malchers F, Menon R, Altmuller J, Becker C, Nurnberg P, Achter V, Lang U, Schneider PM, Bogus M, Soloway MG, Wilkerson MD, Cun Y, McKay JD, Moro-Sibilot D, Brambilla CG, Lantuejoul S, Lemaitre N, Soltermann A, Weder W, Tischler V, Brustugun OT, Lund-Iversen M, Helland A, Solberg S, Ansen S, Wright G, Solomon B, Roz L, Pastorino U, Petersen I, Clement JH, Sanger J, Wolf J, Vingron M, Zander T, Perner S, Travis WD, Haas SA, Olivier M, Foll M, Buttner R, Hayes DN, Brambilla E, Fernandez-Cuesta L, and Thomas RK (2018). Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors. Nat Commun 9, 1048.

    Grimm C, Fischer A, Farrelly AM, Kalachand R, Castiglione R, Wasserburger E, Hussong M, Schultheis AM, Altmuller J, Thiele H, Reinhardt HC, Hauschulz K, Hennessy BT, Herwig R, Lienhard M, Buettner R, and Schweiger MR (2018). Combined Targeted Re-Sequencing of Cytosine DNA Methylation and Mutations of DNA Repair Genes with Potential Use for PARP1 Inhibitor Sensitivity Testing. J Mol Diagn 10.1016/j.jmoldx.2018.10.007.

    Herling CD, Abedpour N, Weiss J, Schmitt A, Jachimowicz RD, Merkel O, Cartolano M, Oberbeck S, Mayer P, Berg V, Thomalla D, Kutsch N, Stiefelhagen M, Cramer P, Wendtner CM, Persigehl T, Saleh A, Altmuller J, Nurnberg P, Pallasch C, Achter V, Lang U, Eichhorst B, Castiglione R, Schafer SC, Buttner R, Kreuzer KA, Reinhardt HC, Hallek M, Frenzel LP, and Peifer M (2018). Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia. Nat Commun 9, 727.

    Horn M, Kroef V, Allmeroth K, Schuller N, Miethe S, Peifer M, Penninger JM, Elling U, and Denzel MS (2018). Unbiased compound-protein interface mapping and prediction of chemoresistance loci through forward genetics in haploid stem cells. Oncotarget 9, 9838-9851.

    Jachimowicz RD, Beleggia F, Isensee J, Velpula BB, Goergens J, Bustos MA, Doll MA, Shenoy A, Checa-Rodriguez C, Wiederstein JL, Baranes-Bachar K, Bartenhagen C, Hertwig F, Teper N, Nishi T, Schmitt A, Distelmaier F, Ludecke HJ, Albrecht B, Kruger M, Schumacher B, Geiger T, Hoon DSB, Huertas P, Fischer M, Hucho T, Peifer M, Ziv Y, Reinhardt HC, Wieczorek D, and Shiloh Y (2018). UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors. Cell10.1016/j.cell.2018.11.024.

    Knittel G, Rehkamper T, Nieper P, Schmitt A, Flumann R, and Reinhardt HC (2018). DNA damage pathways and B-cell lymphomagenesis. Curr Opin Hematol 25, 315-22.

    Meder L, Schuldt P, Thelen M, Schmitt A, Dietlein F, Klein S, Borchmann S, Wennhold K, Vlasic I, Oberbeck S, Riedel R, Florin A, Golfmann K, Schlosser HA, Odenthal M, Buttner R, Wolf J, Hallek M, Herling M, von Bergwelt-Baildon M, Reinhardt HC, and Ullrich RT (2018). Combined VEGF and PD-L1 blockade displays synergistic treatment effects in an autochthonous mouse model of small cell lung cancer. Cancer Res 10.1158/0008-5472.CAN-17-2176.

    Schiller J, Klein S, Engels M, Buttner R, Rybniker J, Fatkenheuer G, Scheid C, Wybranski C, Quaas A, Reinhardt HC, and Flumann R (2018). Case Report: A Cryptosporidium infection in a patient with relapsed T-lymphoblastic lymphoma undergoing allogeneic stem cell transplantation. Eur J Haematol 100, 383-5.

    Schmitt A, Feldmann G, Zander T, and Reinhardt HC (2018). Targeting Defects in the Cellular DNA Damage Response for the Treatment of Pancreatic Ductal Adenocarcinoma. Oncol Res Treat 41, 619-25.

    Schrader A, Crispatzu G, Oberbeck S, Mayer P, Putzer S, von Jan J, Vasyutina E, Warner K, Weit N, Pflug N, Braun T, Andersson EI, Yadav B, Riabinska A, Maurer B, Ventura Ferreira MS, Beier F, Altmuller J, Lanasa M, Herling CD, Haferlach T, Stilgenbauer S, Hopfinger G, Peifer M, Brummendorf TH, Nurnberg P, Elenitoba-Johnson KSJ, Zha S, Hallek M, Moriggl R, Reinhardt HC, Stern MH, Mustjoki S, Newrzela S, Frommolt P, and Herling M (2018). Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL. Nat Commun 9, 697.

    Torgovnick A, Heger JM, Liaki V, Isensee J, Schmitt A, Knittel G, Riabinska A, Beleggia F, Laurien L, Leeser U, Jungst C, Siedek F, Vogel W, Klumper N, Nolte H, Wittersheim M, Tharun L, Castiglione R, Kruger M, Schauss A, Perner S, Pasparakis M, Buttner R, Persigehl T, Hucho T, Herter-Sprie GS, Schumacher B, and Reinhardt HC (2018a). The Cdkn1a(SUPER) Mouse as a Tool to Study p53-Mediated Tumor Suppression. Cell Rep 25, 1027-39 e6.

    Torgovnick A, Schiavi A, Shaik A, Kassahun H, Maglioni S, Rea SL, Johnson TE, Reinhardt HC, Honnen S, Schumacher B, Nilsen H, and Ventura N (2018b). BRCA1 and BARD1 mediate apoptotic resistance but not longevity upon mitochondrial stress in Caenorhabditis elegans. EMBO Rep 19.

    Weber ANR, Cardona Gloria Y, Cinar O, Reinhardt HC, Pezzutto A, and Wolz OO (2018). Oncogenic MYD88 mutations in lymphoma: novel insights and therapeutic possibilities. Cancer Immunol Immunother 67, 1797-807.

    Welcker D, Jain M, Khurshid S, Jokic M, Hohne M, Schmitt A, Frommolt P, Niessen CM, Spiro J, Persigehl T, Wittersheim M, Buttner R, Fanciulli M, Schermer B, Reinhardt HC, Benzing T, and Hopker K (2018). AATF suppresses apoptosis, promotes proliferation and is critical for Kras-driven lung cancer. Oncogene 37, 1503-18.

    Yang D, Denny SK, Greenside PG, Chaikovsky AC, Brady JJ, Ouadah Y, Granja JM, Jahchan NS, Lim JS, Kwok S, Kong CS, Berghoff AS, Schmitt A, Reinhardt HC, Park KS, Preusser M, Kundaje A, Greenleaf WJ, Sage J, and Winslow MM (2018). Intertumoral Heterogeneity in SCLC Is Influenced by the Cell Type of Origin. Cancer Discov 8, 1316-31.

    Bragelmann J, Dammert MA, Dietlein F, Heuckmann JM, Choidas A, Bohm S, Richters A, Basu D, Tischler V, Lorenz C, Habenberger P, Fang Z, Ortiz-Cuaran S, Leenders F, Eickhoff J, Koch U, Getlik M, Termathe M, Sallouh M, Greff Z, Varga Z, Balke-Want H, French CA, Peifer M, Reinhardt HC, Orfi L, Keri G, Ansen S, Heukamp LC, Buttner R, Rauh D, Klebl BM, Thomas RK, and Sos ML (2017). Systematic Kinase Inhibitor Profiling Identifies CDK9 as a Synthetic Lethal Target in NUT Midline Carcinoma. Cell Rep 20, 2833-45.

    George J, Saito M, Tsuta K, Iwakawa R, Shiraishi K, Scheel AH, Uchida S, Watanabe SI, Nishikawa R, Noguchi M, Peifer M, Jang SJ, Petersen I, Buttner R, Harris CC, Yokota J, Thomas RK, and Kohno T (2017). Genomic Amplification of CD274 (PD-L1) in Small-Cell Lung Cancer. Clin Cancer Res 23, 1220-6.

    Knittel G, Rehkamper T, Korovkina D, Liedgens P, Fritz C, Torgovnick A, Al-Baldawi Y, Al-Maarri M, Cun Y, Fedorchenko O, Riabinska A, Beleggia F, Nguyen PH, Wunderlich FT, Ortmann M, Montesinos-Rongen M, Tausch E, Stilgenbauer S, L PF, Herling M, Herling C, Bahlo J, Hallek M, Peifer M, Buettner R, Persigehl T, and Reinhardt HC (2017). Two mouse models reveal an actionable PARP1 dependence in aggressive chronic lymphocytic leukemia. Nat Commun 8, 153.

    Layer JP, Kronmuller MT, Quast T, van den Boorn-Konijnenberg D, Effern M, Hinze D, Althoff K, Schramm A, Westermann F, Peifer M, Hartmann G, Tuting T, Kolanus W, Fischer M, Schulte J, and Holzel M (2017). Amplification of N-Myc is associated with a T-cell-poor microenvironment in metastatic neuroblastoma restraining interferon pathway activity and chemokine expression. Oncoimmunology 6, e1320626.

    Malchers F, Ercanoglu M, Schutte D, Castiglione R, Tischler V, Michels S, Dahmen I, Bragelmann J, Menon R, Heuckmann JM, George J, Ansen S, Sos ML, Soltermann A, Peifer M, Wolf J, Buttner R, and Thomas RK (2017). Mechanisms of Primary Drug Resistance in FGFR1-Amplified Lung Cancer. Clin Cancer Res 23, 5527-36.

    Mollaoglu G, Guthrie MR, Bohm S, Bragelmann J, Can I, Ballieu PM, Marx A, George J, Heinen C, Chalishazar MD, Cheng H, Ireland AS, Denning KE, Mukhopadhyay A, Vahrenkamp JM, Berrett KC, Mosbruger TL, Wang J, Kohan JL, Salama ME, Witt BL, Peifer M, Thomas RK, Gertz J, Johnson JE, Gazdar AF, Wechsler-Reya RJ, Sos ML, and Oliver TG (2017). MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition. Cancer Cell 31, 270-85.

    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.

    Former Funding Period 01/2017 - 12/2019

    Information from this funding period will not be updated anymore. New research related information is available here.

    CMMC Funding Period 1/2020-12/2022

    Christian Reinhardt | Ron Jachimowicz - A 10

    Exploring the efficacy of PARP1 inhibition and anti-PD1 treatment for UBQLN4-overexpressing KRAS-driven lung adenocarcinoma

    Martin Peifer - assoc. RG 16

    Computational cancer genomics

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

    Dept. for Translational Genomics - CMMC Research Building

    CMMC - PI - assoc. 16

    +49 221 478 96863

    +49 221 478 97902

    Dept. for Translational Genomics - CMMC Research Building

    Robert-Koch-Str. 21

    50931 Cologne

    CMMC Profile Page

    Curriculum Vitae (CV)

    Publications on PubMed

    Publications - Martin Peifer

    Link to PubMed


    KFO 286


    Curriculum Vitae - H Christian Reinhardt
    Publications - H Christian Reinhardt

    Link to PubMed


    KFO 286

    Group Members

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