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Abstract

Alexander Deutsch, Clinical Division of Hematology, Medical university of Graz

Supervisor: PD Dr. Alexander Deutsch
Availability: This position is available.
Offered by: Medical University of Graz
Application deadline:Applications are accepted between August 14, 2020 00:00 and October 10, 2020 23:59 (Europe/Zurich)

Description

Background:

Aggressive lymphomas represent the most common type of lymphoid malignancies with a five-year survival rate of 60%. Despite effective initial treatment, one-third of all patients will experience a relapse, warranting more research to discover novel therapeutic strategies. We have previously published a comprehensive study on NR4A nuclear receptor expression analysis in lymphoid neoplasms that revealed a marked reduction of all three members -namely NR4A1, NR4A2, and NR4A3- in the majority of aggressive lymphoma patients. Interestingly, functional characterization demonstrated that NR4A1 and NR4A3 induce apoptosis of aggressive lymphoma cells by regulating a similar pattern of pro-apoptotic genes in vitro and suppresses tumor growth in a xenograft model. For NR4A1, we additionally observed that loss of this gene leads to a marked acceleration of lymphomagenesis in vivo, concomitant with increased expression of immune checkpoints. Immuno-competent, but not immune-deficient, mice transplanted with Nr4a1-deficient lymphoma cells also exhibited rapid lymphoma development, reduced survival, and upregulation of immune checkpoints.

Hypothesis and Objectives:

These data indicate that NR4A1, NR4A2, and NR4A3 have a redundant tumor-suppressive function in lymphomagenesis and that all three members are possibly involved in the regulation of the immune checkpoint-mediated immune evasion. Therefore, we will determine: (1) the effects NR4A3 loss in combination with or without a B cell-specific NR4A1 and/or NR4A2 in Myc-driven lymphomagenesis using transgenic mouse models; (2) the target genes of all three nuclear receptors by combing RNA- and ChIP-Seq analyses; (3) the regulatory function of NR4A1, NR4A2, and NR4A3 on the checkpoint mediated immune evasion in co-culture experiments and immune-competent and -deficient mouse models.

Methodology:

  • Transgenic mouse models
  • Western blot analysis
  • FACS analysis – B cell development and tumor microenvironment
  • RNA- and ChIP-Seq
  • Immune-lymphoma co-culture experiment
  • Immune cell-mediated lysis
  • Transplantation experiments

References:

  1. Fechter K. Feichtinger J., Prochazka K., Unterluggauer JJ., Pansy K., Steinbauer E., Pichler M., Haybaeck J., Prokesch A, Greinix HT., Beham-Schmid C., Neumeister P., Thallinger GG, Deutsch AJA*: Cytoplasmic location of NR4A1 in aggressive lymphomas is associated with a favourable cancer specific survival. Sci Rep. 2018 Sep 28;8(1):14528.
  2. Deutsch, AJA*; Rinner, B; Pichler, M; Prochazka, K; Pansy, K; Bischof, M; Fechter, K; Hatzl, S; Feichtinger, J; Wenzl, K; Frisch, MT; Stiegelbauer, V; Prokesch, A; Krogsdam, A; Sill, H; Thallinger, GG; Greinix, HT; Wang, C; Beham-Schmid, C; Neumeister, P: NR4A3 Suppresses Lymphomagenesis through Induction of Proapoptotic Genes. Cancer Res. 2017; 77(9).
  3. Deutsch, AJ; Rinner, B; Wenzl, K; Pichler, M; Troppan, K; Steinbauer, E; Schwarzenbacher, D; Reitter, S; Feichtinger, J; Tierling, S; Prokesch, A; Scheideler, M; Krogsdam, A; Thallinger, GG; Schaider, H; Beham-Schmid, C; Neumeister, P: NR4A1-mediated apoptosis suppresses lymphomagenesis and is associated with a favorable cancer-specific survival in patients with aggressive B-cell lymphomas. Blood. 2014; 123(15): 2367-2377.
  4. Wenzl, K; Troppan, K; Neumeister, P; Deutsch, AJ*: The Nuclear Orphan Receptor NR4A1 and NR4A3 as Tumor Suppressors in Hematologic Neoplasms. Curr Drug Targets. 2015; 16(1):38-46
  5. Deutsch, AJ; Angerer, H; Fuchs, TE; Neumeister, P: The nuclear orphan receptors NR4A as therapeutic target in cancer therapy. Anticancer Agents Med Chem. 2012; 12(9):1001-1014