TRR 54:  Growth and Survival, Plasticity and Cellular Interactivity of Lymphatic Malignancies

• Subject Area: Medicine
• Term: from 2008 to 2012
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 34712712

• Final Report Year: 2013

Final Report Abstract

The Transregional Collaborative Research Center TRR 54 started as a Berlin-Munich network program in 2008 with the scientific mission to dissect and interconnect the multiple dimensions of lymphoma biology, namely “Growth and Survival, Plasticity and Cellular Interactivity in Lymphoid Malignancies”. Over up to five years, 29 principal investigators (PIs) studied in 18 Work Packages (WP) and 3 Central Packages (CP) in a highly interdisciplinary and interrelated fashion clinically demanding, mechanistically un(der)explored and therapeutically relevant scientific aspects of these “multiple dimensions”. Specifically, three research areas – (A) “Growth, Survival and Failsafe Mechanisms”, (B) “Plasticity and Regulation of Differentiation”, and (C) “Cellular Interactivity: Tumor/Stroma/Altered Tumor Interactions”, all supported by a core area (Z) “Central Tasks of the TRR 54” – reflect the scientific architecture of the collaborative research center. With a defined focus on distinct B- cell malignancies – i.e. aggressive B-cell lymphomas such as diffuse large B-cell lymphoma and Burkitt’s lymphoma, chronic lymphocytic leukemia, multiple myeloma, and Hodgkin’s lymphoma – all WP addressed clinically relevant questions related to cellular integrity (safeguard programs from apoptosis via autophagy to senescence; area A), to cellular plasticity and transdifferentiation (covering stemness, reprogramming and potentially aberrant specialization; area B), and to cellular cross-talk (tumor-host and tumor-tumor interactions; area C). While assigned to these respective areas for structural reasons, many projects were set up to actually bridge and interconnect these areas, which, in their entirety, build the overarching theme of the “multiple dimensions of lymphoma biology”. Importantly, (molecular-)pathological and bioinformatics expertise provided by the Z area facilitated translation to the human condition and ensured that data produced in individual WP were centrally collected, processed and made available to the entire consortium (wherever needed) via the central TRR 54 data base “Lymphoma Explorer”. In essence, this network initiative was an extraordinarily successful scientific endeavor. First and foremost, the output on internationally truly visible, high-ranked publications by the TRR 54 after its first funding period is very remarkable: based on the first two or the last three author positions held by a TRR 54 PI (with typically multiple TRR 54 PIs on the author board), ten papers have been published in the absolute top-league of scientific journals with an impact factor >20, for instance in Nature, Cancer Cell (several), Nature Genetics, or Nature Medicine, and another 15 papers were reported in journals with an impact factor >15. Most publications were made possible by collaborations between PIs from different WP, and many underscore the specific support of the TRR 54 as a transregional instrument with coauthors from both partner sites. Beyond publications, the scientific interaction between Berlin and Munich in general (including TRR 54 meetings, workshops and international guest speaker invitations) and among the scientists – i.e. the PIs, but also the postdoctoral fellows and graduate students – was (and is!) very intense and stimulating. Clearly, many projects or experimental strategies would not have been successfully accomplished without a specific technical application (e.g. rodent PET imaging with novel tracers), a certain piece of equipment (such as the TRR 54-granted BioImager), or a unique expertise (such as lymphoma-tailored bioinformatics tools) provided as an added value of this CRC. Moreover, the academic careers of the PIs developed very well; several PIs were offered upgrades of their current or novel professorships, which came, at least in part, as a consequence of their successful participation in the TRR 54. Although we still struggle with the small number of female investigators, the TRR 54 boosted the establishment of numerous young investigator groups in the lymphoma field at both partner sites. Driven by the TRR 54-related structural achievements regarding the local research environments, the international recognition of the entire consortium, and the extremely fruitful scientific interactions between TRR 54 PIs at and between partner sites, intense collaborative lymphoma research activities remain and will serve as the basis of a lymphoma-centered re-conceptualized network initiative in the near future.

Publications

• Aberrant expression of Notch1 interferes with the B-lymphoid phenotype of neoplastic B cells in classical Hodgkin lymphoma. Leukemia 22, 1587-94 (2008)
  Jundt, F., Acikgöz, O., Kwon, S.H., Schwarzer, R., Anagnostopoulos, I., Wiesner, B., Mathas, S., Hummel, M., Stein, H., Reichardt, H.M., and Dörken, B.
  
• Aberrant expression of the Th2 cytokine IL-21 in Hodgkin lymphoma cells regulates STAT3 signaling and attracts T-reg cells via regulation of MIP-3 alpha. Blood 112, 3339-3347 (2008)
  Lamprecht, B., Kreher, S., Anagnostopoulos, I., Jöhrens, K., Monteleone, G., Jundt, F., Stein, H., Janz, M., Dörken, B. and Mathas, S.
  
• Constitutive CD40 signaling in B cells selectively activates the noncanonical NF-kappaB pathway and promotes lymphomagenesis. J Exp Med 205, 1317-1329 (2008)
  Homig-Holzel, C., Hojer, C., Rastelli, J., Casola, S., Strobl, L.J., Muller, W., Quintanilla- Martinez, L., Gewies, A., Ruland, J., Rajewsky, K., and Zimber-Strobl, U.
  
• Histone acetylation and DNA demethylation of B cells result in a Hodgkin-like phenotype. Leukemia 22(4), 835 (2008)
  Ehlers, A., Oker, E., Bentink, S., Lenze, D., Stein, H., and Hummel, M.
  
• Immunogenicity of premalignant lesions is the primary cause of general cytotoxic T lymphocyte unresponsiveness. J Exp Med 205, 1687 (2008)
  Willimsky, G., Czeh, M., Loddenkemper, C., Gellermann, J., Schmidt, K., Wust, P., Stein, H., and Blankenstein, T.
  
• LMP1 signaling can replace CD40 signaling in B cells in vivo and has unique features of inducing class-switch recombination to IgG1. Blood 111, 1448-1455. (2008)
  Rastelli, J., Homig-Holzel, C., Seagal, J., Muller, W., Hermann, A.C., Rajewsky, K., and Zimber-Strobl, U.
  
• Notch inhibition blocks multiple myeloma cell-induced osteoclast activation. Leukemia 22, 2273-7 (2008)
  Schwarzer, R., Kaiser, M., Acikgoez, O., Heider, U., Mathas, S., Preissner, R., Sezer, O., Doerken, B. and Jundt, F.
  
• A nuclear poly (ADP-ribose) dependent signalosome confers DNA damage induced IκB kinase activation. Mol Cell 36, 365-378 (2009)
  Stilmann, M., Hinz, M., Çöl Arslan, S., Zimmer, A., Schreiber, V., and Scheidereit, C.
  
• DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction. Nat Genet 41, 1207 (2009)
  Bröske, A.M., Vockentanz, L., Kharazi, S., Huska, M., Mancini, E., Scheller, M., Enns, A., Prinz, M., Jaenisch, R., Nerlov, C., Leutz, A., Andrade-Navarro, M.A., Jacobsen, S.E., and Rosenbauer, F.
  
• Functional identification of tumor-suppressor genes through an in vivo RNA interference screen in a mouse lymphoma model. Cancer Cell 16, 324-35 (2009)
  Bric, A., Miething, C., Bialucha, C.U., Scuoppo, C., Zender, L., Krasnitz, A., Xuan, Z., Zuber, J., Wigler, M., Hicks, J., McCombie, R.W., Hemann, M.T., Hannon, G.J., Powers, S., and Lowe, S.W.
  
• Gene deregulation and spatial genome reorganization near breakpoints prior to formation of translocations in anaplastic large cell lymphoma. Proc Natl Acad Sci USA 106, 5831-5836 (2009)
  Mathas, S., Kreher, S., Meaburn, K.J., Jöhrens, K., Lamprecht, B., Assaf, C., Sterry, W., Kadin, M.E., Daibata, M., Joos, S., Hummel, M., Stein, H., Janz, M., Anagnostopoulos, I., Schrock, E., Misteli, T., and Dörken, B.
  
• Notch1, Notch2, and Epstein-Barr virus-encoded nuclear antigen 2 signaling differentially affects proliferation and survival of Epstein-Barr virusinfected B cells. Blood 113, 5506-5515 (2009)
  Kohlhof, H., Hampel, F., Hoffmann, R., Burtscher, H., Weidle, U.H., Holzel, M., Eick, D., Zimber-Strobl, U., and Strobl, L.J.
  
• A cytoplasmic ATM-TRAF6-cIAP1 module links nuclear DNA damage signaling to ubiquitinmediated NF-κB activation. Mol Cell 40, 63-74 (2010)
  Hinz, M., Stilmann, M., Çöl Arslan, S., Khanna, K.K., Dittmar, G., and Scheidereit, C.
  
• Aurora kinases A and B are up-regulated by Myc and are essential for maintenance of the malignant state. Blood 116, 1498 (2010)
  den Hollander, J., Rimpi, S., Doherty, J.R., Rudelius, M., Buck, A., Hoellein, A., Kremer, M., Graf, N., Scheerer, M., Hall, M.A., Goga, A., von Bubnoff, N., Duyster, J., Peschel, C., Cleveland, J.L., Nilsson, J.A., and Keller, U.
  
• Derepression of an endogenous long terminal repeat activates the CSF1R proto-oncogene in human lymphoma. Nat Med 16, 571-579 (2010)
  Lamprecht, B., Walter, K., Kreher, S., Kumar, R., Hummel, M., Lenze, D., Köchert, K., Bouhlel, M.A., Richter, J., Soler, E., Stadhouders, R., Jöhrens, K., Wurster, K.D., Callen, D.F., Harte, M.F., Giefing, M., Barlow, R., Stein, H., Anagnostopoulos, I., Janz, M., Cockerill, P.N., Siebert, R., Dörken, B., Bonifer, C., and Mathas, S.
  
• Early B Cell Factor 2 Regulates Hematopoietic Stem Cell Homeostasis in a Cell-Nonautonomous Manner. Cell Stem Cell 7 496-507 (2010)
  Kieslinger, M., Hiechinger, S., Dobreva, G., Consalez, G.G., and Grosschedl, R.
  
• Recruitment of PKC-βII to lipid rafts mediates apoptosis-resistance in chronic lymphocytic leukemia expressing ZAP-70. Leukemia 24, 141-152 (2010)
  Meyer zum Büschenfelde, C., Wagner, M., Lutzny, G., Oelsner, M., Feuerstacke, Y., Decker, T., Bogner, C., Peschel, C., and Ringshausen, I.
  
• The fusion kinase ITK-SYK mimics a T cell receptor signal and drives oncogenesis in conditional mouse models of peripheral T cell lymphoma. J Exp Med 207, 1031-1044. (2010)
  Pechloff, K., Holch, J., Ferch, U., Schweneker, M., Brunner, K., Kremer, M., Sparwasser, T., Quintanilla-Martinez, L., Zimber-Strobl, U., Streubel, B., Gewies, A., Peschel, C., and Ruland, J.
  
• Tumor stroma-derived TGF-beta limits mycdriven lymphomagenesis via Suv39h1-dependent senescence. Cancer Cell 17, 262-272 (2010)
  Reimann, M., Lee, S., Loddenkemper, C., Dörr, J.R., Tabor, V., Aichele, P., Stein, H., Dörken, B., Jenuwein, T., and Schmitt, C.A.
  
• CD19-independent instruction of murine marginal zone B-cell development by constitutive Notch2 signaling. Blood 118, 6321-6331 (2011)
  Hampel, F., Ehrenberg, S., Hojer, C., Draeseke, A., Marschall-Schroter, G., Kuhn, R., Mack, B., Gires, O., Vahl, C.J., Schmidt-Supprian, M., Strobl, L.J., and Zimber-Strobl, U.
  
• Genomic loss of the putative tumor suppressor gene E2A in human lymphoma. J Exp Med 208, 1585-1593 (2011)
  Steininger, A., Möbs, M., Ullmann, R., Köchert, K., Kreher, S., Lamprecht, B., Anagnostopoulos, I., Hummel, M., Richter, J., Beyer, M., Janz, M., Klemke, C.D., Stein, H., Dörken, B., Sterry, W., Schrock, E., Mathas, S., and Assaf, C.
  
• Immune modulation by Fas ligand reverse signaling: lymphocyte proliferation is attenuated by the intracellular Fas ligand domain. Blood 117, 519-529 (2011)
  Luckerath, K., Kirkin, V., Melzer, I.M., Thalheimer, F.B., Siele, D., Milani, W., Adler, T., Aguilar-Pimentel, A., Horsch, M., Michel, G., Beckers, J., Busch, D.H., Ollert, M., Gailus- Durner, V., Fuchs, H., Hrabe de Angelis, M., Staal, F.J., Rajalingam, K., Hueber, A.O., Strobl, L.J., Zimber-Strobl, U. and Zörnig, M.
  
• Opposing roles of NF-κB in anti-cancer treatment outcome unveiled by cross-species investigations. Genes Dev. 25, 2137-2146 (2011)
  Jing, H., Kase, J., Dörr, J.R., Milanovic, M., Lenze, D., Grau, M., Beuster, G., Ji, S., Reimann, M., Lenz, P., Hummel, M., Dörken, B., Lenz, G., Scheidereit, C., Schmitt, C.A., and Lee, S.
  
• Sorafenib induces cell death in chronic lymphocytic leukaemia by translational downregulation of Mcl-1. Leukemia 25, 838-837 (2011)
  Huber, S., Oelsner, M., Decker, T., Meyer zu Büschenfelde, C., Wagner, M., Lutzny, G., Kuhnt, T., Schmidt, B., Oostendorp, R., Peschel, C. and Ringshausen, I.
  
• Two distinct auto-regulatory loops operate at the Pu.1 locus in B cells and myeloid cells. Blood 117, 2827 (2011)
  Leddin, M., Perrod, C., Hoogenkamp, M., Ghani, S., Assi, S., Heinz, S., Wilson, N.K., Follows, G., Schönheit, J., Vockentanz, l., Mosammam, A.M., Chen, W., Tenen, D.G., Westhead, D.R., Göttgens, B., Bonifer, C., and Rosenbauer, F.
  
• Syk kinase-coupled C-type lectin receptors engage protein kinase C-sigma to elicit Card9 adaptor-mediated innate immunity. Immunity 36, 32-42 (2012)
  Strasser, D., Neumann, K., Bergmann, H., Marakalala, M. J., Guler, R., Rojowska, A., Hopfner, K. P., Brombacher, F., Urlaub, H., Baier, Brown, G.D., Leitges, M., and Ruland, J.
  
• A homozygous mucosaassociated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency. J Allergy Clin Immunol 132, 151-158 (2013)
  Jabara, H. H., Ohsumi, T., Chou, J., Massaad, M. J., Benson, H., Megarbane, A., Chouery, E., Mikhael, R., Gorka, O., Gewies, A., Portales, P., Nakayama, T., Hosokawa, H., Revy, P., Herrod, H., Le Deist, F., Lefranc, G., Ruland, J., and Geha, R.S.
  
• Differently immunogenic cancers in mice induce immature myeloid cells that suppress CTL in vitro but not in vivo following transfer. Blood 121, 1740-1748 (2013)
  Schmidt, K., Zilio, S., Schmollinger, J.C., Bronte, V., Blankenstein, T., and Willimsky, G.
  
• Fas expression by tumor stroma is required for cancer eradication. Proc Natl Acad Sci U S A 110, 2276-2281 (2013)
  Listopad, J.J., Kammertoens, T., Anders, K., Silkenstedt, B., Willimsky, G., Schmidt, K., Kühl, A., Loddenkemper, C., and Blankenstein, T.
  
• PAX5 overexpression is not enough to re-establish the mature B-cell phenotype in classical Hodgkin lymphoma. Leukemia (2013)
  Dimitrova, L., Seitz, V., Hecht, J., Lenze, D., Hansen, P., Szczepanowski, M., Ma, L., Oker, E., Sommerfeld, A., Jundt, F., Klapper, W., and Hummel, M.
  
• Protein kinase c-beta-dependent activation of NF- kappaB in stromal cells is indispensable for the survival of chronic lymphocytic leukemia B cells in vivo. Cancer Cell 23, 77-92. (2013)
  Lutzny, G., Kocher, T., Schmidt-Supprian, M., Rudelius, M., Klein-Hitpass, L., Finch, A.J., Durig, J., Wagner, M., Haferlach, C., Kohlmann, A., Schnittger, S., Seifert, M., Wanninger, S., Zaborsky, N., Oostendorp, R., Ruland, J., Leitges, M., Kuhnt, T., Schäfer, Y., Lampl, B., Peschel, C., Egle, A., and Ringshausen, I.
  
• Synthetic lethal metabolic targeting of cellular senescence in cancer therapy. Nature 501, 421-425 (2013)
  Dörr, J.R., Yu, Y., Milanovic, M., Beuster, G., Zasada, C., Däbritz, J.H., Lisec, J., Lenze, D., Gerhardt, A., Schleicher, K., Kratzat, S., Purfürst, B., Walenta, S., Mueller-Klieser, W., Gräler, M., Hummel, M., Keller, U., Buck, A.K., Dörken, B., Willmitzer, L., Reimann, M., Kempa, S., Lee S., and Schmitt, C.A.