Expression of the potential therapeutic target CXXC5 in primary acute myeloid leukemia cells - high expression is associated with adverse prognosis as well as altered intracellular signaling and transcriptional regulation

Øystein Bruserud,Amir Kadi,Tuyen Thy Van Hoang,Audrey Astori,Jørn Skavland,Annette K Brenner,Frederic Pendino,Hanne Fredly,Karen-Marie Hagen,Bjørn Tore Gjertsen,Håkon Reikvam

doi:10.18632/oncotarget.3056

Abstract

The CXXC5 gene encodes a transcriptional activator with a zinc-finger domain, and high expression in human acute myeloid leukemia (AML) cells is associated with adverse prognosis. We now characterized the biological context of CXXC5 expression in primary human AML cells. The global gene expression profile of AML cells derived from 48 consecutive patients was analyzed; cells with high and low CXXC5 expression then showed major differences with regard to extracellular communication and intracellular signaling. We observed significant differences in the phosphorylation status of several intracellular signaling mediators (CREB, PDK1, SRC, STAT1, p38, STAT3, rpS6) that are important for PI3K-Akt-mTOR signaling and/or transcriptional regulation. High CXXC5 expression was also associated with high mRNA expression of several stem cell-associated transcriptional regulators, the strongest associations being with WT1, GATA2, RUNX1, LYL1, DNMT3, SPI1, and MYB. Finally, CXXC5 knockdown in human AML cell lines caused significantly increased expression of the potential tumor suppressor gene TSC22 and genes encoding the growth factor receptor KIT, the cytokine Angiopoietin 1 and the selenium-containing glycoprotein Selenoprotein P. Thus, high CXXC5 expression seems to affect several steps in human leukemogenesis, including intracellular events as well as extracellular communication.

Highlights

CXXC5 is a retinoid-responsive gene localized to the 5q31.3 chromosomal region [1] and encoding a retinoid-inducible nuclear factor (RINF) [2] that is a protein containing a CXXC-type zinc-finger domain and acting as a transcription regulator [3]
We recently described that CXXC5 is expressed in primary acute myeloid leukemia (AML) cells; this expression shows a wide variation between patients and high levels are associated with an adverse prognosis and resistance to chemotherapy-induced apoptosis [4]
When comparing the 34 patients with low and the 33 patients with high CXXC5 expression we confirmed that monocytic differentiation of the leukemic cells (FAB-M4/M5) was associated with low expression compared with neutrophilic differentiation (FAB-M2) [4], whereas CXXC5HIGH and CXXC5LOW patients did not differ significantly for any other parameter, including the percentage of patients with at least one risk factor for chemoresistance

Summary

Introduction

CXXC5 is a retinoid-responsive gene localized to the 5q31.3 chromosomal region [1] and encoding a retinoid-inducible nuclear factor (RINF) [2] that is a protein containing a CXXC-type zinc-finger domain and acting as a transcription regulator [3]. Expression studies as well as gene silencing experiments suggest that CXXC5 is important in normal myelopoiesis [2] and for differentiation of endothelial cells [3]. Another study recently confirmed our observations and CXXC5 expression was of independent prognostic significance in multivariate analyses after adjustment www.impactjournals.com/oncotarget for age, white blood cell count, cytogenetic risk group, FLT3-ITD status, biallelic CEBPA mutations, as well as mutations of NPM1, DNMT3A and ASXL1 [5]. Based on these observations we suggest that CXXC5 should be considered as a possible therapeutic target in human AML. In the present study we characterized the biological context of high CXXC5 expression and effects of CXXC5 knockdown in human AML cells

Methods

Results

Conclusion