DEK oncogene expression during normal hematopoiesis and in Acute Myeloid Leukemia (AML)

Abstract

DEK is important in regulating cellular processes including proliferation, differentiation and maintenance of stem cell phenotype. The translocation t(6;9) in Acute Myeloid Leukemia (AML), which fuses DEK with NUP214, confers a poor prognosis and a higher risk of relapse. The over-expression of DEK in AML has been reported, but different studies have shown diminished levels in pediatric and promyelocytic leukemias. This study has characterized DEK expression, in silico, using a large multi-center cohort of leukemic and normal control cases. Overall, DEK was under-expressed in AML compared to normal bone marrow (NBM). Studying specific subtypes of AML confirmed either no significant change or a significant reduction in DEK expression compared to NBM. Importantly, the similarity of DEK expression between AML and NBM was confirmed using immunohistochemistry analysis of tissue mircorarrays. In addition, stratification of AML patients based on median DEK expression levels indicated that DEK showed no effect on the overall survival of patients. DEK expression during normal hematopoiesis did reveal a relationship with specific cell types implicating a distinct function during myeloid differentiation. Whilst DEK may play a potential role in hematopoiesis, it remains to be established whether it is important for leukemagenesis, except when involved in the t(6;9) translocation.

The DEK oncoprotein is upregulated by multiple leukemia-associated fusion genes

“…The expression of DEK has long been considered upregulated also in AML, based on two studies using quantitative PCR analysis to demonstrate overexpression in cohorts of 15 and 41 patients [7,8]. However, in a recent study in this journal, Logan et al showed similar expression levels in normal and malignant hematopoietic cells in an in silico analysis of a large pre-existing dataset, verified by tissue microarray [9].…”

Neuroanatomical Distribution of DEK Protein in Corticolimbic Circuits Associated with Learning and Memory in Adult Male and Female Mice

“…Aberrant expression or localization of the DEK DNA-binding protein has been associated with several diseases, including acute myeloid leukemia (Logan et al 2015, Von Lindern et al 1992), various types of solid tumors (Piao et al 2014, Privette Vinnedge et al 2015, Wang et al 2014), and as an auto-antigen in numerous auto-immune diseases, most notably juvenile idiopathic arthritis (Mor-Vaknin et al 2011, Sierakowska et al 1993, Szer et al 1994). DEK (human 6p22.3) is a unique protein, with no known homologs, that preferentially binds supercoiled and cruciform DNA in vitro .…”

A role for intracellular and extracellular DEK in regulating hematopoiesis

“…Upon examination of DEK mRNA levels in HSCs/HPCs and mature myeloid lineage cells, it was discovered that DEK expression was elevated in HSCs and HPCs when compared to mature granulocytic and monocytic populations in both human and mice [1, 43]. However, peak DEK expression levels varied between mice and man [1]. The greatest DEK expression in humans occurred in HSCs with a steady decline in expression levels as the cells differentiated into HPCs then matured into polymononuclear cells (PMNs) and monocytes.…”

“…DEK was originally discovered as part of the fusion protein DEK-NUP214 (i.e. DEK-CAN), a result of a t(6;9) chromosome translocation in a subset of patients with acute myelogenous leukemia [1–4*], and as an oncoprotein in various neoplasms including melanoma [5–7*], breast cancer [8], glioblastoma [9], hepatocellular carcinoma [10, 11*], retinoblastoma [12, 13], gastric adenocarcinoma [14*], non-small cell lung cancer [15*], pancreatic ductal adenocarcinoma [16*], and bladder cancer [17]. DEK was found to be a regulator of hematopoiesis controlling HSC and HPC numbers/fate decision [18, 19].…”