Molecular Genetics

Our research deals with the identification and characterization of novel oncogenes in lymphatic malignancies, including T-cell leukemia and Hodgkin lymphoma. The work is focused on deregulated homeobox genes and their regulatory networks in these disease entities.

Homeobox genes encode transcription factors which interact with DNA in a sequence specific manner and with other coregulating proteins. They regulate important processes in development including differentiation, proliferation and survival. Therefore, many homeobox genes have been described to be deregulated in different types of cancer. 

In T-cell acute lymphoid leukemia (T-ALL) cell lines we have identified deregulated homeobox gene NKX2-5, recognizing the involvement of the NK-like family (NKL) of homeobox genes which includes the well-known members TLX1 and TLX3 in this disease. Comprehensive analysis of all human NKL homeobox genes identified physiologically expressed members of this family in hematopoietic stem cells and in lymphopoiesis (Table 1). These data prompted us to create the term NKL-code for the activity pattern of hematopoietic homeobox genes of this group. This approach has been extended to describe normal and abnormal activities of NKL homeobox genes in the complete hematopoietic system. 

Aberrantly expressed NKL homeobox genes like MSX1 might contribute to the development of hematopoietic malignancies (Fig. 1), representing an oncogene in T-ALL and a tumor suppressor gene in NK-cell leukemia (Fig. 2 +3). Downstream analyses for NK-like homeobox genes identified MEF2C and the micro-RNA cluster miR17~92. Gene networks deregulated by homeobox genes in cancer may represent a basic scaffold, the knowledge of which may contribute to the development of promising interventions.

Selected References

  1. Nagel S, Uphoff CC, Dirks WG, Pommerenke C, Meyer C, Drexler HG. Epstein-Barr virus (EBV) activates NKL homeobox gene HLX in DLBCL. PLoS One. 2019;14(5):e0216898.
  2. Nagel S, Pommerenke C, Macleod RAF, Meyer C, Kaufmann M, Fähnrich S, Drexler HG. Deregulated expression of NKL homeobox genes in T-cell lymphomas. Oncotarget 2019; 10(35):3227-3247. 
  3. Nagel S, MacLeod RAF, Meyer C, Kaufmann M, Drexler HG. NKL homeobox gene activities in B-cell development and lymphomas. PLoS One. 2018;13(10):e0205537.
  4. Nagel S, Pommerenke C, Meyer C, Kaufmann M, Macleod RAF, Drexler HG. NKL homeobox gene MSX1 acts like a tumor suppressor in NK-cell leukemia. Oncotarget 2017;8(40):66815-66832. 
  5. Nagel S, Pommerenke C, Scherr M, Meyer C, Kaufmann M, Battmer K, Macleod RAF, Drexler HG. NKL homeobox gene activities in hematopoietic stem cells, T-cell development and T-cell leukemia. PLoS One. 2017; 12(2):e0171164. 
  6. Nagel S, Pommerenke C, Meyer C, Kaufmann M, Drexler HG, Macleod RAF. Deregulation of Polycomb Repressor Complex 1 modifier AUTS2 in T-cell leukemia. Oncotarget. 2016; 7(29):45398-45413. 
  7. Nagel S, Ehrentraut S, Meyer C, Kaufmann M, Drexler HG, Macleod RAF. Repressed BMP signaling reactivates NKL homeobox gene MSX1 in a T-ALL subset. Leuk Lymphoma. 2015; 56(2):480-491. 
  8. Nagel S, Ehrentraut S, Tomasch J, Quentmeier H, Meyer C, Kaufmann M, Drexler HG, and MacLeod RAF. Ectopic expression of homeobox gene NKX2-1 in diffuse large B-cell lymphoma is mediated by aberrant chromatin modifications. PLoS One. 2013; 8(4):e61447. 
  9. Nagel S, Venturini L, Przybylski GK, Grabarczyk P, Meyer C, Kaufmann M, Schmidt CA, Scherr M, Drexler HG, MacLeod RAF. Activation of paired-homeobox gene PITX1 by del(5)(q31) in T-cell acute lymphoblastic leukemia (T-ALL). Leuk Lymphoma 2011; 52(7):1348-1359. 
  10. Nagel S, Venturini L, Przybylski GK, Grabarczyk P, Schmidt CA, Meyer C, Drexler HG, Macleod RA, Scherr M. Activation of miR-17-92 by NK-like homeodomain proteins suppresses apoptosis via reduction of E2F1 in T-cell acute lymphoblastic leukemia. Leuk Lymphoma. 2009; 50(1):101-108. 
  11. Nagel S, Meyer C, Quentmeier H, Kaufmann M, Drexler HG, MacLeod RA. MEF2C is activated by multiple mechanisms in a subset of T-acute lymphoblastic leukemia cell lines. Leukemia. 2008; 22(3):600-607.
  12. Nagel S, Burek C, Venturini L, Scherr M, Quentmeier H, Meyer C, Rosenwald A, Drexler HG, MacLeod RA. Comprehensive analysis of homeobox genes in Hodgkin lymphoma cell lines identifies dysregulated expression of HOXB9 mediated via ERK5 signaling and BMI1. Blood. 2007; 109(7):3015-3023. 
  13. Nagel S, Kaufmann M, Drexler HG, MacLeod RA. The cardiac homeobox gene NKX2-5 is deregulated by juxtaposition with BCL11B in pediatric T-ALL cell lines via a novel t(5;14)(q35.1;q32.2). Cancer Res. 2003; 63(17):5329-5334.