Contact

 

Dr. Stefan Gröschel
Phone: +49 6221 42 1613
E-mail: stefan.groeschel(at)nct-heidelberg.de

Molecular Leukemogenesis

DKFZ
 
 
 

ChIP-seq and 4C-seq (middle panel) in myeloid blast cells (left panel) nominates a candidate EVI1 superenhancer, that can be targeted by CRISPR/Cas9. Deletion of the superenhancer leads to monocytic differentiation of blast cells.

Our scientific objectives are to understand pathways of gene regulation and to develop insights with innovate technologies to control gene expression in cancers driven by EVI1, most prominently acute myeloid leukemia. Together with collaboratives from our group and industry alliances we aim to translate these ideas as cancer therapeutic strategies.
Regulated expression of genes is orchestrated by surrounding control sequences, so-called „enhancers“. Enhancers can engage with target genes in different 3D nuclear chromatin interaction networks and function as cell type specific switches depending on tissue context, resulting in distinct gene expression programs that maintain cellular identity. This regulatory principle is exploited by oncogenes during tumorigenesis by 3D reorganization of enhancer-gene communications (enhancer hijacking). These physical interactions are either induced by gross chromosomal alterations (inversions, translocations, amplifications) or more subtle changes to the DNA code or even as aberrant dynamic chromatin changes without disruption of the linear DNA template.
Deregulation of the EVI1 oncogene is a key transforming event in the development of many malignancies and was initially discovered in high-risk leukemias, but remains largely unexplored in other entities, for example soft tissue sarcoma and other solid organ cancers. Both EVI1 function and the mechanism underlying its deregulation are poorly understood and the consequent lack of a targeted therapy against EVI1 creates a formidable clinical challenge. By applying functional genome diagnostics (next-generation sequencing-based, e.g. ChIP, targeted locus proteomics, 4C chromatin analysis) and genome editing (CRISPR technology) we aim to explore ways to reprogram the cancer cell's fundamental identity and revert the aggressive phenotype of these EVI1+ cancers. Toward these goals, we are also part of the ENHANCE consortium of the DKFZ, a highly interactive joint research collaboration of investigators from the DKFZ involved in basic and translational research with a focus on epigenetics.

Our group has:

  • Demonstrated that EVI1 overexpression is an independent risk factor in acute myeloid leukemia (Gröschel et al. J Clin Oncol 2010; Lugthart and Gröschel et al., J Clin Oncol 2010; Gröschel et al., J. Clin Oncol 2013)
  • Showed that “enhancer hijacking” defines a subtype of leukemia (Gröschel et al. Cell 2014)
  • Identified that activating signaling mutations are common in the high-risk AML subtype inv(3)/t(3;3) (Gröschel et al., Blood 2015)

2010-2015

  • Gröschel S*, Sanders MA*, Hoogenboezem R, Zeilemaker A, Havermans M, Erpelinck C, Bindels EMJ, Beverloo HB, Döhner H, Löwenberg B, Döhner K, Delwel R, Valk PJM. Mutational spectrum of myeloid malignancies with inv(3)/t(3;3) reveals a predominant involvement of RAS/RTK signaling pathways. (*contributed equally)
    Blood 2015 Jan 1:125(1):133-139.

  • Gröschel S*, Sanders M*, Hoogenboezem R, de Wit E, Bouwman B, Erpelinck C, van der Velden V, Havermans M, Avellino R, van Lom K, Rombouts E, van Duin M, Döhner K, Beverloo B, Bradner J, Döhner H, Löwenberg B, Valk P, Bindels E, de Laat W, Delwel R. A single oncogenic enhancer rearrangement causes concomitant deregulation of EVI1 and GATA2 in leukemia. (*contributed equally)
    Cell 2014 Apr 10; 157(2):369-81.

  • Gröschel S, Schlenk RF, Engelmann J, Rockova V, Teleanu V, Kühn MW, Eiwen K, Erpelinck C, Havermans M, Lübbert M, Germing U, Schmidt-Wolf IG, Beverloo HB, Schuurhuis GJ, Ossenkoppele GJ, Schlegelberger B, Verdonck LF, Vellenga E, Verhoef G, Vandenberghe P, Pabst T, Bargetzi M, Krauter J, Ganser A, Valk PJ, Löwenberg B, Döhner K, Döhner H*, Delwel R*. Deregulated expression of EVI1 defines a poor prognostic subset of MLL-rearranged acute myeloid leukemias: a study of the German-Austrian Acute Myeloid Leukemia Study Group and the Dutch-Belgian-Swiss HOVON/SAKK Cooperative Group. (*contributed equally)
    J Clin Oncol 2013 Jan 1;31(1):95-103.

  • Lugthart S*, Gröschel S*, Beverloo HB, Kayser S, Valk PJM, Van Zelderen-Bhola S, Ossenkoppele GJ, Vellenga E, van den Berg-de Ruiter E, Schanz U, Verhoef G, Ferrant A, Köhne CH, Pfreundschuh M, Horst HA, Koller E, von Lilienfeld-Toal M, Bentz M, Ganser A, Schlegelberger B, Jotterand M, Krauter J, Pabst T, Theobald M, Schlenk RF, Delwel R, Döhner K, Löwenberg B* and Döhner H*. Clinical, molecular, and prognostic significance of WHO type inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and various other 3q abnormalities in acute myeloid leukemia: A study of 6,500 cases of AML. (*contributed equally)
    J Clin Oncol 2010 Aug 20; 28(24):3890-8.

  • Gröschel S*, Lugthart S*, Schlenk RF, Valk PJ, Eiwen K, Goudswaard C, van Putten WJ, Kayser S, Verdonck LF, Lübbert M, Ossenkoppele GJ, Germing U, Schmidt-Wolf I, Schlegelberger B, Krauter J, Ganser A, Döhner H, Löwenberg B, Döhner K*, Delwel R*. High EVI1 expression predicts outcome in younger adult patients with acute myeloid leukemia and is associated with distinct cytogenetic abnormalities. (*contributed equally)
    J Clin Oncol 2010 Apr 20;28(12):2101-7.

Sabrina Hettinger
Lab manager, Technician
sabrina.hettinger(at)nct-heidelberg.de

Sandra Kiehlmeier
PhD Student
sandra.kiehlmeier(at)nct-heidelberg.de

Sabrina Kruse
PhD Student
sabrina.kruse(at)nct-heidelberg.de

Dr. Asha Das
Postdoc
asha.das(at)nct-heidelberg.de

Jagoda Mika
PhD Student
jagoda.mika(at)nct-heidelberg.de