Concise review: role of DEK in stem/progenitor cell biology

Abstract

Understanding the factors that regulate hematopoiesis opens up the possibility of modifying these factors and their actions for clinical benefit. DEK, a non-histone nuclear phosphoprotein initially identified as a putative proto-oncogene, has recently been linked to regulate hematopoiesis. DEK has myelosuppressive activity in vitro on proliferation of human and mouse hematopoietic progenitor cells and enhancing activity on engraftment of long-term marrow repopulating mouse stem cells, has been linked in coordinate regulation with the transcription factor C/EBPα, for differentiation of myeloid cells, and apparently targets a long-term repopulating hematopoietic stem cell for leukemic transformation. This review covers the uniqueness of DEK, what is known about how it now functions as a nuclear protein and also as a secreted molecule that can act in paracrine fashion, and how it may be regulated in part by dipeptidylpeptidase 4, an enzyme known to truncate and modify a number of proteins involved in activities on hematopoietic cells. Examples are provided of possible future areas of investigation needed to better understand how DEK may be regulated and function as a regulator of hematopoiesis, information possibly translatable to other normal and diseased immature cell systems.

Keywords: Chromatin; DEK; Dipeptidylpeptidase IV; Hematopoietic progenitor cells; Hematopoietic stem cells; Receptors.

Figure 1

Schematic depiction of the structure, functional domains and post-translational modifications of DEK, potential DEK uptake pathways, and effects of DEK on hematopoiesis. A) Linear sequence of DEK with DNA binding domains (yellow: pseudo-SAP-box; green: SAP-box; blue: C-terminal DNA-binding domain; orange lines: position of α-helices, as revealed by NMR), and other functional features (red: acidic regions; black: putative NLS) indicated [See references 25,41,42,44,45]. The positions of previously mapped phosphorylation and acetylation sites are marked [See references , and 15]. B) Potential DEK receptor mediated and/or uptake pathways. C) Simplified depiction of DEK functions in the setting of chromatin. DEK interacts with, and augments binding of HP1 to H3K9Me3, thereby recruiting SUV39H1/2, thus further enhancing the deposition of H3K9Me3. In addition, DEK binds to DNA/chromatin via its DNA binding domains (see A). However, the precise consequences for open or closed chromatin currently remains elusive. D) Functional consequences of DEK in the setting of hematopoietic stem (HSC) and progenitor (HPC) cells. Not shown is the potential influence of Dipeptidylpeptidase 4 truncation of DEK on DEK functional activity.

Figure 2

Effects of DEK knockout (−/−) on hematopoietic progenitor cells. Results are shown for these cells in S-phase of the cell cycle, as determined by high specific activity tritiated thymidine kill technique, when stimulated with 5% pokeweed mitogen spleen cell conditioned medium (PWMSCM), SCF (50ng/ml), and EPO (1U/ml) in methylcellulose culture (A) and when stimulated with GM-CSF (10ng/ml) alone and in combination with SCF in agar culture (B) [6]. Results are given as mean±1SEM of 3 mice per group. *, significantly different from control medium (p<0.05), as assessed by 2 tailed t test.

Figure 3

Influence of DPP4 on DEK activity. Shown are effects of full length (FL) – and DPP4-treated (=likely truncated, TR) DEK, alone and in combination, on 5×104 C57Bl/6 mouse BM cells/ml pretreated with Diprotin A, an inhibitor of DPP4, and stimulated with GM-CSF (Exp#1) or GM-CSF+SCF (Exp#2) (See reference for details of such studies done with other growth modulating proteins). Results are given as mean±1SEM. *, significantly different from control medium (p<0.05); ND= not done

Figure 4

Influence of DEK on colony formation by human factor dependent cell lines MO7e and TF1. These cells were not pretreated with a DPP4 inhibitor. Results are shown as mean±1SEM for 1000 MO7e and 500 TF1 cells/ml −/+ 1 hour pulse treatment of these cell lines with control medium or 50nM DEK prior to their stimulation with GM-CSF plus SCF (See reference for details of such studies done with the TF1 human growth factor dependent cell line assessing the effects of other proteins on colony formation). *, significantly different from control medium (p<0.05)