The topic of our research covers identification and characterization of novel oncogenes in hematopoietic malignancies. The work is focused on deregulated homeobox genes which encode transcription factors and are part of regulatory networks in leukemia and lymphoma. These transcription factors interact with DNA in a sequence specific manner and cooperate with other proteins. Homeobox genes control basic processes in development including differentiation, proliferation and survival, thus contributing to cancerogenesis if deregulated.
In T-cell acute lymphoid leukemia (T-ALL) cell lines we have identified deregulated homeobox gene NKX2-5, recognizing the involvement of the NKL subclass of homeobox genes. This discovery prompted us to extend the search for additional deregulated NKL homeobox genes in various types of hematopoietic malignancies. Furthermore, we analyzed the physiological expression pattern of these genes in human hematopoiesis, creating the term „NKL-code“ for normal gene activities in this system (Fig. 1).
The NKL-code enables differentiation between normal and abnormal expression of NKL homeobox genes and may serve as diagnostic platform to evaluate leukemia and lymphoma subsets. Cell lines expressing deregulated NKL homeobox genes represent suitable tools to examine upstream and downstream factors generating regulatory networks for these genes. Summarizing results from recent studies about deregulated NKL homeobox genes HMX2/HMX3 in acute myeloid leukemia (AML) and HLX in anaplastic large cell lymphoma (ALCL) are shown in Fig. 2 and Fig. 3, respectively. Moreover, the concept of hematopoietic transcription factor codes was extended and includes the class of TALE homeobox genes, generating the „TALE-code“.
- Nagel S. NKL-code in normal and aberrant hematopoiesis. Cancers (Basel). 2021;13(1961)
Nagel S, Pommerenke C, Meyer C, MacLeod RAF, Drexler HG. Aberrant expression of NKL homeobox genes HMX2 and HMX3 interferes with cell differentiation in acute myeloid leukemia. PloS One 2020;15(10):e0240120.
Nagel S, Pommerenke C, MacLeod RAF, Meyer C, Kaufmann M, Drexler HG. The NKL-code for innate lymphoid cells reveals deregulated expression of NKL homeobox genes HHEX and HLX in anaplastic large cell lymphoma (ALCL). Oncotarget 2020;11(34):3208-3226.
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.
- 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.