Characterization of chronic myeloid leukemia stem cells

Authors

  • Jonathan M. Gerber,

    Corresponding author
    1. Division of Hematology, Department of Medicine, The Johns Hopkins University School of Medicine and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
    • The Bunting-Blaustein Cancer Research Bldg, Room 205, 1650 Orleans St., Baltimore, MD 21231
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  • Lu Qin,

    1. Department of Oncology, The Johns Hopkins University School of Medicine and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
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  • Jeanne Kowalski,

    1. Department of Oncology, The Johns Hopkins University School of Medicine and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
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  • B. Douglas Smith,

    1. Department of Oncology, The Johns Hopkins University School of Medicine and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
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  • Constance A. Griffin,

    1. Department of Pathology, The Johns Hopkins University School of Medicine and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
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  • Milada S. Vala,

    1. Department of Oncology, The Johns Hopkins University School of Medicine and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
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  • Michael I. Collector,

    1. Department of Oncology, The Johns Hopkins University School of Medicine and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
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  • Brandy Perkins,

    1. Department of Oncology, The Johns Hopkins University School of Medicine and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
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  • Marianna Zahurak,

    1. Department of Oncology, The Johns Hopkins University School of Medicine and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
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  • William Matsui,

    1. Department of Oncology, The Johns Hopkins University School of Medicine and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
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  • Christopher D. Gocke,

    1. Department of Pathology, The Johns Hopkins University School of Medicine and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
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  • Saul J. Sharkis,

    1. Department of Oncology, The Johns Hopkins University School of Medicine and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
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  • Hyam I. Levitsky,

    1. Department of Oncology, The Johns Hopkins University School of Medicine and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
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  • Richard J. Jones

    1. Department of Oncology, The Johns Hopkins University School of Medicine and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
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Abstract

Although tyrosine kinase inhibitors have redefined the care of chronic myeloid leukemia (CML), these agents have not proved curative, likely due to resistance of the leukemia stem cells (LSC). While a number of potential therapeutic targets have emerged in CML, their expression in the LSC remains largely unknown. We therefore isolated subsets of CD34+ stem/progenitor cells from normal donors and from patients with chronic phase or blast crisis CML. These cell subsets were then characterized based on ability to engraft immunodeficient mice and expression of candidate therapeutic targets. The CD34+CD38 CML cell population with high aldehyde dehydrogenase (ALDH) activity was the most enriched for immunodeficient mouse engrafting capacity. The putative targets: PROTEINASE 3, SURVIVIN, and hTERT were expressed only at relatively low levels by the CD34+CD38ALDHhigh CML cells, similar to the normal CD34+CD38ALDHhigh cells and less than in the total CML CD34+ cells. In fact, the highest expression of these antigens was in normal, unfractionated CD34+ cells. In contrast, PRAME and WT1 were more highly expressed by all CML CD34+ subsets than their normal counterparts. Thus, ALDH activity appears to enrich for CML stem cells, which display an expression profile that is distinct from normal stem/progenitor cells and even the CML progenitors. Indeed, expression of a putative target by the total CD34+ population in CML does not guarantee expression by the LSC. These expression patterns suggest that PROTEINASE 3, SURVIVIN, and hTERT are not optimal therapeutic targets in CML stem cells; whereas PRAME and WT1 seem promising. Am. J. Hematol., 2011. © 2010 Wiley-Liss, Inc.

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