title: Genome-wide comparison of the transcriptomes of highly enriched normal and chronic myeloid leukemia stem and progenitor cell populations.
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 (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.
authors: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.
authors: Jonathan M
authors: JM
authors: Gerber
authors: Jessica L
authors: JL
authors: Gucwa
authors: David
authors: D
authors: Esopi
authors: Meltem
authors: M
authors: Gurel
authors: Michael C
authors: MC
authors: Haffner
authors: Milada
authors: M
authors: Vala
authors: William G
authors: WG
authors: Nelson
authors: Richard J
authors: RJ
authors: Jones
authors: Srinivasan
authors: S
authors: Yegnasubramanian
mesh_terms: D052004:Bone Morphogenetic Protein Receptors / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics; D015536:Down-Regulation; D020869:Gene Expression Profiling; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000166:cytology*; D015398:Signal Transduction / Q000235:genetics; D013234:Stem Cells / Q000166:cytology*; D059467:Transcriptome / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: C111835:CCL2 protein, human; C530104:CCND1 protein, human; D018932:Chemokine CCL2; D016212:Transforming Growth Factor beta; D019938:Cyclin D1; D052004:Bone Morphogenetic Protein Receptors
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