Molecular Genetics

Hematopoietic cell lines represent useful models to identify and characterize novel oncogenes in leukemia and lymphoma. The topic of our research is focused on deregulated homeobox genes which encode transcription factors, controlling basic processes in development as well as proliferation and survival.

In T-cell acute lymphoid leukemia (T-ALL) cell lines we have identified aberrantly activated homeobox gene NKX2-5, recognizing the involvement of the NKL subclass of homeobox genes in this type of leukemia. 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 compartment (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 are suitable tools to examine upstream and downstream factors generating aberrant regulatory networks. Summarizing results from our recent studies about deregulated NKL homeobox gene HLX is shown in Fig. 2.

Moreover, we have extended the concept of hematopoietic transcription factor codes and included the class of TALE homeobox genes, generating the „TALE-code“ (Fig. 3). According to this code, IRX1 is physiologically expressed in both, B-cell progenitors and megakaryocyte erythroid progenitors (MEPs). Evaluation of corresponding malignancies revealed aberrant expression of IRX1 and the related genes IRX2, IRX3 and IRX5 in patients and cell lines from precursor B-cell acute lymphoblastic leukemia (PBC-ALL) and AML, respectively. Upstream and downstream activities of these IRX members in normal and aberrant B-cell development and myelopoiesis are shown in Figure 4.


Selected References

  1. Nagel S.  NKL-code in normal and aberrant hematopoiesis. Cancers (Basel). 2021;13(1961)
  2. Nagel S. The NKL- and TALE-codes represent hematopoietic gene signatures to evaluate deregulated homeobox genes in Hodgkin lymphoma. Hemato 2022;3:122-130.

  3. Nagel S, Pommerenke C, Meyer C, MacLeod RAF. The hematopoietic TALE-Code shows normal activity of IRX1 in myeloid progenitors and reveals ectopic expression of IRX3 and IRX5 in acute myeloid leukemia. Int J Mol Sci. 2022;23(6):3192.

  4. Nagel S, Meyer C. Normal and aberrant TALE-class homeobox gene activities in pro-B-cells and B-cell precursor acute lymphoblastic leukemia. Int J Mol Sci. 2022;23(19):11874.

  5. Nagel S., The role of IRX homeobox genes in hematopoietic progenitors and leukemia. Genes 2023;14:297.