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

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...

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Published in:Oncotarget 2013-05, Vol.4 (5), p.715-728
Main Authors: Gerber, Jonathan M, Gucwa, Jessica L, Esopi, David, Gurel, Meltem, Haffner, Michael C, Vala, Milada, Nelson, William G, Jones, Richard J, Yegnasubramanian, Srinivasan
Format: Article
Language:English
Subjects:
Bone Morphogenetic Protein Receptors - metabolism
Cell Differentiation - genetics
Cell Proliferation
Chemokine CCL2 - metabolism
Cyclin D1 - metabolism
DNA Repair - genetics
Down-Regulation
Gene Expression Profiling
Humans
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics
Neoplastic Stem Cells - cytology
Research Papers
Signal Transduction - genetics
Stem Cells - cytology
Transcriptome - genetics
Transforming Growth Factor beta - metabolism
Tumor Cells, Cultured
Up-Regulation
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Summary: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 (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 these cells and achieve cure.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.990