Oncotarget

Research Papers:

Genome-wide comparison of the transcriptomes of highly enriched normal and chronic myeloid leukemia stem and progenitor cell populations

Jonathan M. Gerber, Jessica L. Gucwa, David Esopi, Meltem Gurel, Michael C. Haffner, Milada Vala, William G. Nelson, Richard J. Jones and Srinivasan Yegnasubramanian _

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Oncotarget. 2013; 4:715-728. https://doi.org/10.18632/oncotarget.990

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Abstract

Jonathan M. Gerber1,*, Jessica L. Gucwa2,*, David Esopi2, Meltem Gurel2, Michael C. Haffner2, Milada Vala2, William G. Nelson2, Richard J. Jones2, and Srinivasan Yegnasubramanian2

1 Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD

2 The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, School of Medicine, Baltimore, MD, USA

* These authors contributed equally to this work.

Correspondence:

Srinivasan Yegnasubramanian, email:

Keywords: chronic myeloid leukemia, CML, leukemic stem cell, LSC, normal hematopoietic stem cell, HSC, myeloid progenitor cells, CD34, CD38, ALDH, IL2RA, CD25, DPP4, CD26, GAS2

Received: April 19, 2013 Accepted: May 5, 2013 Published: May 6, 2013

Abstract

The persistence leukemia stem cells (LSCs) in chronic myeloid leukemia (CML) despite tyrosine kinase inhibition (TKI) may explain relapse after TKI withdrawal. Here we performed genome-wide transcriptome analysis of highly refined CML and normal stem and progenitor cell populations to identify novel targets for the eradication of CML LSCs using exon microarrays. We identified 97 genes that were differentially expressed in CML versus normal stem and progenitor cells. These included cell surface genes significantly upregulated in CML LSCs: DPP4 (CD26), IL2RA (CD25), PTPRD, CACNA1D, IL1RAP, SLC4A4, and KCNK5. Further analyses of the LSCs revealed dysregulation of normal cellular processes, evidenced by alternative splicing of genes in key cancer signaling pathways such as p53 signaling (e.g. PERP, CDKN1A), kinase binding (e.g. DUSP12, MARCKS), and cell proliferation (e.g. MYCN, TIMELESS); downregulation of pro-differentiation and TGF-β/BMP signaling pathways; upregulation of oxidative metabolism and DNA repair pathways; and activation of inflammatory cytokines, including CCL2, and multiple oncogenes (e.g. CCND1). These data represent an important resource for understanding the molecular changes in CML LSCs, which may be exploited to develop novel therapies for eradication of these cells and to achieve cure.


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