Hematopoietic cell lines represent useful models to identify and characterize novel oncogenes in corresponding entities of leukemia and lymphoma. The topic of our research is focused on gene families encoding related transcription factors (TF), which control basic processes in hematopoietic development. Aberrant activities of particular developmental TFs may underlie hematopoietic carcinogenesis.
In a first step, we analyze physiological expression patterns of all family members in human hematopoietic stem cells, progenitor cells, and mature immune and blood cells. The generated datasets describe normal TF gene activities for the hematopoietic compartment and are termed TF-codes. According to the analyzed TF gene family, we have established the “NKL-code”, “TALE-code” and “CUT-code” for homeodomain TFs, and the “ETS-code” and “TBX-code” for ETS-factors and T-box factors, respectively [1-3].
In the next step, comparison of these physiological activities with public expression data from leukemia/lymphoma patients reveals deregulated TF-encoding genes for each family in particular disease entities. Subsequent screening of our published RNA-seq data may detect corresponding cell lines which aberrantly express identified genes of interest and serve as models to reveal mechanisms of deregulation, target genes, and the oncogenic role of this TF.
Figure 1 shows all entities of the hematopoietic compartment and TALE-class homeobox gene activities for each cell type, thus representing the TALE-code. Of note, the activity of TALE-class member IRX1 is restricted to the pro-B-cell progenitor in the lymphoid B-cell lineage, and to the megakaryocyte-erythroid-progenitor (MEP) in the myeloid lineage. Deregulated IRX1 or IRX1-related genes in B-cell progenitor acute lymphoid leukemia (BCP-ALL) or in acute myeloid leukemia (AML) may, therefore, impact developmental processes at these susceptible stages and support leukemogenesis.
According to this model, we have reported aberrant expression of IRX1-related genes IRX2 and IRX3 in BCP-ALL [4,5], and MKX in AML [6]. Figure 2 and Figure 3 summarize the reported results for these novel oncogenes, showing upstream regulators and downstream activities, which may have implications for diagnostic and therapies in the clinic.
Fig. 1: Hematopoietic TALE-code highlighting homeobox gene IRX1. This diagram depicts activities of TALE homeobox genes during early hematopoiesis, in lymphopoiesis including development of T-cells, B-cells, NK-cells and ILCs, and in myelopoiesis. Each cell/stage is labelled with the accordingly expressed NKL homeobox genes. BCP: B-cell progenitor, cDC: conventional dendritic cells, CDP: common dendritic cell progenitor, CILP: common innate lymphoid progenitor, CLP: common lymphoid progenitor, CMP: common myeloid progenitor, DC: dendritic cell, DN: double negative, DP: double positive, ETP: early T-cell progenitor, GC B-cell: germinal center B-cell, GMP: granulocytic-monocytic progenitor, HSC: hematopoietic stem cell, ILC(P): innate lymphoid cell (progenitor), LMP: lymphoid and myeloid primed progenitor, memo B-cell: memory B-cell, MEP: megakaryocyte-erythroid-progenitor, pDC: plasmacytoid dendritic cells. IRX1 is indicated by a blue arrowhead.
Fig. 2: IRX1-related TALE-class homeobox genes IRX2 and IRX3 in BCP-ALL. The developmental stages pro-B and pre-B represent the cells of origin for BCP-ALL. Based on our reported expression data termed TALE-code, NKL-code, EST-code and TBX-code we have analyzed regulatory connections between these genes which are shown in blue. Oncogenic fusion-genes and aberrantly expressed TALE-class members IRX2 and IRX3 are shown in brown.
Fig. 3: IRX1-related TALE-class homeobox gene MKX in AML. Aberrantly expressed homeobox gene MKX is shown centrally in blue. Activating factors include JUNB, NFkB and IRX5, while downregulated factors STAT5 and GATA2 are repressors. Target genes of MKX are CCL2, BCL2L11, SESN3, CEBPD and GATA2, involved in proliferation, apoptosis and differentiation.
Citations
- Nagel S. NKL-code in normal and aberrant hematopoiesis. Cancers (Basel) 2021;13(8):1961.
- Nagel S., The role of IRX homeobox genes in hematopoietic progenitors and leukemia. Genes 2023;14:297.
- Nagel S, Rand U, Pommerenke C, Meyer C. Transcriptional landscape of CUT-class homeobox genes in blastic plasmacytoid dendritic cell neoplasm. Int J Mol Sci. 2024;25(5):2764.
- 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.
- Nagel S, Meyer C. Identification of gene regulatory networks in B-cell progenitor differentiation and leukemia. Genes 2024;15(8):978.
- Nagel S, Meyer C, Pommerenke C. IRX-related homeobox gene MKX is a novel oncogene in acute myeloid leukemia. PlosOne 2024;19(12):e0315196.
