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Acute Leukemias

Gene expression profiling in the leukemic stem cell-enriched CD34+ fraction identifies target genes that predict prognosis in normal karyotype AML

Abstract

In order to identify acute myeloid leukemia (AML) CD34+-specific gene expression profiles, mononuclear cells from AML patients (n=46) were sorted into CD34+ and CD34 subfractions, and genome-wide expression analysis was performed using Illumina BeadChip Arrays. AML CD34+ and CD34 gene expression was compared with a large group of normal CD34+ bone marrow (BM) cells (n=31). Unsupervised hierarchical clustering analysis showed that CD34+ AML samples belonged to a distinct cluster compared with normal BM and that in 61% of the cases the AML CD34+ transcriptome did not cluster together with the paired CD34 transcriptome. The top 50 of AML CD34+-specific genes was selected by comparing the AML CD34+ transcriptome with the AML CD34 and CD34+ normal BM transcriptomes. Interestingly, for three of these genes, that is, ankyrin repeat domain 28 (ANKRD28), guanine nucleotide binding protein, alpha 15 (GNA15) and UDP-glucose pyrophosphorylase 2 (UGP2), a high transcript level was associated with a significant poorer overall survival (OS) in two independent cohorts (n=163 and n=218) of normal karyotype AML. Importantly, the prognostic value of the continuous transcript levels of ANKRD28 (OS hazard ratio (HR): 1.32, P=0.008), GNA15 (OS HR: 1.22, P=0.033) and UGP2 (OS HR: 1.86, P=0.009) was shown to be independent from the well-known risk factors FLT3-ITD, NPM1c+ and CEBPA mutation status.

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Acknowledgements

This study was supported by a grant from the ‘Innovatie Fonds’ UMCG, The Netherlands. We would like to acknowledge Prof. Dr B Löwenberg and Dr PJM Valk (Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands) for providing clinical data of the NK AML gene expression set and for critical reading of the manuscript.

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Correspondence to E Vellenga or J J Schuringa.

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de Jonge, H., Woolthuis, C., Vos, A. et al. Gene expression profiling in the leukemic stem cell-enriched CD34+ fraction identifies target genes that predict prognosis in normal karyotype AML. Leukemia 25, 1825–1833 (2011). https://doi.org/10.1038/leu.2011.172

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