AG Raffel - Emmy Noether Programm
„Metabolic Vulnerabilities of Acute Myeloid Leukemia Stem Cells“
Welcome to the Raffel laboratory
Our goal is to discover targetable metabolic vulnerabilities in Leukemic Stem Cells of Acute Myeloid Leukemia in order to improve clinical outcomes of leukemia patients.
Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy, which is characterized by the accumulation of clonal myeloid blast cells unable to differentiate into mature cells. Chemotherapy induces remission in the majority of patients but relapse rates are very high and lead to poor clinical outcomes. Relapse and therapy failure are caused by chemotherapy-resistant leukemic stem cells (LSCs) and in order to improve patient survival, it is essential to eradicate LSCs. Targeting aberrant immunophenotypes of LSCs has been the predominant strategy to eliminate LSCs. However, the efficacy of this approach may be limited due to the plasticity of LSC phenotypes. Therefore, modulating more fundamental aspects of LSC biology may represent a comprehensive and effective type of therapy and especially metabolic peculiarities seem to represent an Achilles’ heel of LSCs.
We have identified alpha-ketoglutarate (αKG) as a key metabolite regulating stemness in LSCs via epigenetic and posttranslational mechanisms. αKG is an essential co-substrate for cellular dioxygenases, which control a broad range of cellular functions. Suppression of αKG-dependent enzymes constitutes a common feature of AML and, next to mutations in IDH and TET2, we identified Branched Chain Amino Acid Metabolism as an alternative, non-genetic mechanism in LSCs to control the activity of these enzymes (Figure 1) (Raffel et al., Nature 2017).
We are currently exploring strategies how to manipulate αKG homeostasis in LSCs using hierarchical cell lines and primary AML stem cells as well as healthy hematopoietic stem cells in vitro and in vivo. Technologies include metabolomics, CRISPR screens, xenotransplantation models, and manipulation of activities of genes and enzymes as well as single-cell analyses.
Due to previous technological limitations, the majority of studies in the hematology field are based on assays that require pooling thousands of cells. Therefore, results were mostly derived from complex mixtures of cells and even in functionally defined LSC-fractions true LSC may be a minority and thus LSC-specific signals may be diluted. Only single-cell approaches have the potential to overcome these limitations. We have developed a combined transcriptomic and functional single cell approach to study human hematopoiesis (Figure 2) (Velten*, Haas*, Raffel* et al, Nat Cell Biol 2017). As this technology is able to link transcriptome and function of individual single cells it confers a substantial advantage over commercially available single cell analysis platforms.
We are currently modifying this technology to map metabolic features, transcriptome, function and mutational status at single cell resolution in primary AML samples. This dataset will help to decipher the crosstalk between metabolism, gene expression and function, and enables us to study tumor heterogeneity. Our goal is to detect “real” LSCs and identify their specific metabolic vulnerabilities.
Since 2020 we are part of the Junior research alliance “LeukoSyStem” funded by the German Federal Ministry of Education and Research. Together with our collaborators, we apply novel single cell technologies in order to provide a systematic characterization of both pathogenesis and therapy-resistance mechanisms in AML (https://www.sys-med.de/en/junior-research-alliances/leukosystem/).
Dr. Simon Haas, German Cancer Research Center (DKFZ) and Heidelberg Institute for Stem Cell Technologies and Experimental Medicine (HI-STEM)
Prof. Andreas Trumpp, German Cancer Research Center (DKFZ) and Heidelberg Institute for Stem Cell Technologies and Experimental Medicine (HI-STEM)
Dr. Lars Velten, European Molecular Biology Laboratory (EMBL)
Dr. Laleh Haghverdi, European Molecular Biology Laboratory (EMBL)
Dr. Gernot Poschet, Centre for Organismal Studies, Metabolomics Core Technology Platform (MCTP), Heidelberg University
Dr. Stefano Casola, IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy
We are recruiting highly motivated PhD and MD students. Please contact simon.raffel(at)med.uni-heidelberg.de
S. Raffel*, M. Falcone*, N. Kneisel*, J. Hansson, W. Wang, C. Lutz, L. Bullinger, G. Poschet, Y. Nonnenmacher, A. Barnert, C. Bahr, P. Zeisberger, A. Przybylla, M. Sohn, M. Tonjes, A. Erez, L. Adler, P. Jensen, C. Scholl, S. Frohling, S. Cocciardi, P. Wuchter, C. Thiede, A. Florcken, J. Westermann, G. Ehninger, P. Lichter, K. Hiller, R. Hell, C. Herrmann, A. D. Ho, J. Krijgsveld, B. Radlwimmer and A. Trumpp (2017). BCAT1 restricts alphaKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation. Nature 551(7680): 384-388. *equal contribution
S. Raffel, D. Klimmeck, M. Falcone, A. Demir, A. Pouya, P. Zeisberger, C. Lutz, M. Tinelli, O. Bischel, L. Bullinger, C. Thiede, A. Flörcken, J. Westermann, G.Ehninger, A.D. Ho, C. Müller-Tidow, Z. Gu, C. Herrmann, J. Krijgsveld, A. Trumpp, J. Hansson (2020). Quantitative proteomics reveals specific metabolic features of Acute Myeloid Leukemia stem cells. Blood.136(13):1507-1519p.
AM Paczulla*, K. Rothfelder*, S. Raffel*, M. Konantz, J. Steinbacher, H. Wang, C. Tandler, M. Mbarga, T. Schaefer, M. Falcone, E. Nievergall, D. Dorfel, P. Hanns, JR Passweg, C. Lutz, A. Schwaller, R. Zeiser, BR Blazar, MA Caligiuri, S. Dirnhofer, P. Lundberg, L. Kanz, L. Quintanilla- Martinez, A. Steinle, A. Trumpp, HR Salih, C. Lengerke (2019). Absence of NKG2D ligands defines leukaemia stem cells and mediates their immune evasion. Nature 572(7768):254-259. *equal contribution
L. Velten*, S. F. Haas*, S. Raffel*, S. Blaszkiewicz, S. Islam, B. P. Hennig, C. Hirche, C. Lutz, E. C. Buss, D. Nowak, T. Boch, W. K. Hofmann, A. D. Ho, W. Huber, A. Trumpp, M. A. Essers and L. M. Steinmetz (2017). Human haematopoietic stem cell lineage commitment is a continuous process. Nat Cell Biol 19(4): 271-281. *equal contribution
G. Varano*, S. Raffel*, M. Sormani, F. Zanardi, S. Lonardi, C. Zasada, L. Perucho, V. Petrocelli, A. Haake, A. K. Lee, M. Bugatti, U. Paul, E. Van Anken, L. Pasqualucci, R. Rabadan, R. Siebert, S. Kempa, M. Ponzoni, F. Facchetti, K. Rajewsky and S. Casola (2017). The B-cell receptor controls fitness of MYC-driven lymphoma cells via GSK3beta inhibition. Nature 546(7657): 302-306. *equal contribution
S. Raffel and A. Trumpp (2016). miR-126 Drives Quiescence and Self-Renewal in Leukemic Stem Cells. Cancer Cell 29(2): 133-135.
C. Stockklausner*, S. Raffel*, J. Klermund, O. R. Bandapalli, F. Beier, T. H. Brummendorf, F. Burger, S. W. Sauer, G. F. Hoffmann, H. Lorenz, L. Tagliaferri, D. Nowak, W. K. Hofmann, R. Buergermeister, C. Kerber, T. Rausch, J. O. Korbel, B. Luke, A. Trumpp and A. E. Kulozik (2015). A novel autosomal recessive TERT T1129P mutation in a dyskeratosis congenita family leads to cellular senescence and loss of CD34+ hematopoietic stem cells not reversible by mTOR-inhibition. Aging (Albany NY) 7(11): 911-927. *equal contribution
N. Jager, M. Schlesner, D. T. Jones, S. Raffel, J. P. Mallm, K. M. Junge, D. Weichenhan, T. Bauer, N. Ishaque, M. Kool, P. A. Northcott, A. Korshunov, R. M. Drews, J. Koster, R. Versteeg, J. Richter, M. Hummel, S. C. Mack, M. D. Taylor, H. Witt, B. Swartman, D. Schulte-Bockholt, M. Sultan, M. L. Yaspo, H. Lehrach, B. Hutter, B. Brors, S. Wolf, C. Plass, R. Siebert, A. Trumpp, K. Rippe, I. Lehmann, P. Lichter, S. M. Pfister and R. Eils (2013). Hypermutation of the inactive X chromosome is a frequent event in cancer. Cell 155(3): 567-581.
H. Medyouf, M. Mossner, J. C. Jann, F. Nolte, S. Raffel, C. Herrmann, A. Lier, C. Eisen, V. Nowak, B. Zens, K. Mudder, C. Klein, J. Oblander, S. Fey, J. Vogler, A. Fabarius, E. Riedl, H. Roehl, A. Kohlmann, M. Staller, C. Haferlach, N. Muller, T. John, U. Platzbecker, G. Metzgeroth, W. K. Hofmann, A. Trumpp and D. Nowak (2014). Myelodysplastic cells in patients reprogram mesenchymal stromal cells to establish a transplantable stem cell niche disease unit. Cell Stem Cell 14(6): 824-837.
W. Wang, T. Stiehl, S. Raffel, V. T. Hoang, I. Hoffmann, L. Poisa-Beiro, B. R. Saeed, R. Blume, L. Manta, V. Eckstein, T. Bochtler, P. Wuchter, M. Essers, A. Jauch, A. Trumpp, A. Marciniak-Czochra, A. D. Ho and C. Lutz (2017). Reduced hematopoietic stem cell frequency predicts outcome in acute myeloid leukemia. Haematologica 102(9): 1567-1577.