AG Wichmann

Experimental Cell Therapy & Hematology

AG Wichmann Group Members

Group Members:

Mengdi Yin, MMed, PhD student

Clara Reinhold, PhD student

Nina Koch, MD student

Petra Cesari, MD student

Dr. phil. nat. Linping Chen-Wichmann, Lab-Manager

PD Dr. med. Christian Wichmann, PI

Max-Lebsche-Platz 32
81377 München

Scope:

We use primary human cell models to study normal and leukemic expansion of hematopoietic progenitor cells mediated by epigenetic regulators and oncogenic fusion proteins such as SETBP1, and RUNX1-ETO and MLL-ENL. In addition, we develop retroviral and lentiviral vector systems for the efficient and safe generation of CAR T cells and CAR macrophages.

Methods:

Culture of human CD34+ stem-/progenitor cells. Retroviral transduction and expression of inducible transcription

factors. Long term cultivation in liquid cultures. Differentiation into functional blood cells.

Current Research Topics

Fluorescence microscopy of engulfed tumor cells (green) after co-incubation with human CD34+ stem/progenitor cell derived macrophages.
  • Manufacturing of engineered immune cells in vitro

    In the raising field of cell therapy, we focus on engineering both Chimeric Antigen Receptor (CAR) T cells as well as CAR macrophages in vitro. Our scope is to modify the cells in a way to ensure both strong anti-cancer effects as wells as tight controllability to prevent unwanted side effects. For this, we develop -retro- and lentiviral vectors to stably express transgenes of interest. Furthermore, we aim to establish new methods to warrant large-scale production of immune cells for therapeutical use. 

RUNX1-ETO perturbs gene expression programs in hematopoietic stem and progenitor cells by repressing RUNX1 target genes that are essential for myeloid differentiation. As a consequence, differentiation is blocked and immature progenitor cells accumulate, representing an early step in leukemic transformation.
  • Investigating the role of epigenetic regulators and transcription factors in leukemic cell expansion

During leukemogenesis, transcriptional regulators are frequently altered, resulting in uncontrolled proliferation and impaired differentiation of immature hematopoietic progenitor cells. Two prominent oncogenic fusion proteins arising from chromosomal translocations are RUNX1-ETO and MLL-ENL. To investigate their capacity to drive leukemic expansion, we use retroviral and lentiviral systems to inducibly express these fusion genes in primary human progenitor cells. Our aim is to understand the modular architecture of these fusion proteins and to dissect the molecular mechanisms underlying ex vivo expansion and transformation of hematopoietic progenitor cells.

Literature:

  • Windisch R, Soliman S, Hoffmann A, Chen-Wichmann L, Danese A, Vosberg S, Bravo J, Lutz S, Kellner C, Fischer A, Gebhard C, Redondo Monte E, Hartmann L, Schneider S, Beier F, Strobl CD, Weigert O, Peipp M, Schündeln M, Stricker SH, Rehli M, Bernhagen J, Humpe A, Klump H, Brendel C, Krause DS, Greif PA, Wichmann C. Engineering an inducible leukemia-associated fusion protein enables large-scale ex vivo production of functional human phagocytes. PNAS 2024 Jun 18;121(25):e2312499121. 

  • Xhaxho S, Chen-Wichmann L, Kreissig S, Windisch R, Gottschlich A, Nandi S, Schabernack S, Kohler I, Kellner C, Kobold S, Humpe A, Wichmann C. Efficient CAR T cell generation starting with leukoreduction system chambers of thrombocyte apheresis sets. Transfus Med Hemother 2023 Aug 30;51(2):111-118. 

  • Windisch R, Kreißig S, Wichmann C: Defined Leukemic CD34+ Liquid Cultures to Study HDAC/Transcriptional Repressor Complexes. Methods in Molecular Biology, Springer Nature 2023;2589:27-49.

  • Chen-Wichmann L, Shvartsman M, Preiss C, Hockings C, Windisch R, Redondo-Monte E, Leupolt G, Spiekermann K, Lausen J, Brendel C, Grez M, Greif P, Wichmann C: Compatibility of RUNX1/ETO fusion protein modules driving CD34+ human progenitor cell expansion. Oncogene. 2019, Jan;38(2):261-272.

  • Schanda J, Chun-Wie L, Wohlan K, Müller-Kuller U, Kunkel H, Quagliano-Lo Coco I, Stein S, Metz A, Koch J, Lausen J, Medyouf H, Gohlke H, Heuser M, Eder M, Grez M, Scherr M, and Wichmann C. Suppression of RUNX1/ETO oncogenic activity by a small molecule inhibitor of NHR2 tetramerization. Haematologica. 2017 May;102(5):e170-e174.

  • Ponnusamy K, Kohrs N, Ptasinska A, Assi SA, Herold T, Hiddemann W, Lausen J, Bonifer C, Henschler R, Wichmann C. RUNX1/ETO blocks selectin-mediated adhesion via epigenetic silencing of PSGL-1. Oncogenesis. 2015 Apr 13;4:e146.