The Role of NKL Homeobox Genes in T-Cell Malignancies

Abstract

Homeobox genes encode transcription factors controlling basic developmental processes. The homeodomain is encoded by the homeobox and mediates sequence-specific DNA binding and interaction with cofactors, thus operating as a basic regulatory platform. Similarities in their homeobox sequences serve to arrange these genes in classes and subclasses, including NKL homeobox genes. In accordance with their normal functions, deregulated homeobox genes contribute to carcinogenesis along with hematopoietic malignancies. We have recently described the physiological expression of eleven NKL homeobox genes in the course of hematopoiesis and termed this gene expression pattern NKL-code. Due to the developmental impact of NKL homeobox genes these data suggest a key role for their activity in the normal regulation of hematopoietic cell differentiation including T-cells. On the other hand, aberrant overexpression of NKL-code members or ectopical activation of non-code members has been frequently reported in lymphoid and myeloid leukemia/lymphoma, demonstrating their oncogenic impact in the hematopoietic compartment. Here, we provide an overview of the NKL-code in normal hematopoiesis and discuss the oncogenic role of deregulated NKL homeobox genes in T-cell malignancies.

Keywords: NKL-code; T-all; homeobox; homeodomain; lymphoma.

Figure 1

Schematic structure of NKL homeodomain proteins. N: N-terminal end; C: C-terminal end; EH1: conserved engrailed homology domain consisting of about 8 amino acid residues (shown in green); the conserved homeodomain consists of 60 amino acid residues which generate three helices (H1, H2, H3) and is shown in blue; the N- and C-terminal parts show no sequence conservation. The EH1 domain and the homeodomain interact with particular components of the gene regulatory machinery including corepressors of the TLE family and specific DNA sequences, respectively.

Figure 2

The NKL-code in lymphopoiesis This diagram depicts activities of NKL homeobox genes during early hematopoiesis, in lymphopoiesis including development of T-cells, B-cells, NK-cells and ILCs, and in myelopoiesis. Each cell-type/stage is labelled with the accordingly expressed NKL homeobox genes. BCP: B-cell progenitor, cDC: conventional dendritic cell, CDP: common dendritic progenitor, CILP: common innate lymphoid progenitor, CLP: common lymphoid progenitor, CMP: common myeloid progenitor, 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), LMPP: lymphoid and myeloid primed progenitor, memo B-cell: memory B-cell, MEP: megakaryocyte-erythroid-progenitor, pDC: plasmacytoid dendritic cell. ?: no expression data were available for progenitor stages CLP, NKP, MDP and CDP, ---: no NKL homeobox gene activity detectable.