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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)715-728
Number of pages14
JournalOncotarget
Volume4
Issue number5
StatePublished - May 2013

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Myeloid Progenitor Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Transcriptome
Stem Cells
Genome
Population
Leukemia
Protein-Tyrosine Kinases
Genes
Alternative Splicing
Gene Expression Profiling
Cell- and Tissue-Based Therapy
Oncogenes
DNA Repair
Exons
Phosphotransferases
Up-Regulation
Down-Regulation
Cell Proliferation
Cytokines

Keywords

  • ALDH
  • CD25
  • CD26
  • CD34
  • CD38
  • Chronic myeloid leukemia
  • CML
  • DPP4
  • GAS2
  • HSC
  • IL2RA
  • Leukemic stem cell
  • LSC
  • Myeloid progenitor cells
  • Normal hematopoietic stem cell

ASJC Scopus subject areas

  • Oncology

Cite this

Genome-wide comparison of the transcriptomes of highly enriched normal and chronic myeloid leukemia stem and progenitor cell populations. / Gerber, Jonathan M.; Gucwa, Jessica; Esopi, David; Gurel, Meltem; Haffner, Michael C.; Vala, Milada; Nelson, William G; Jones, Richard J; Yegnasubramanian, S.

In: Oncotarget, Vol. 4, No. 5, 05.2013, p. 715-728.

Research output: Contribution to journalArticle

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