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    Functional ramifications for the loss of P-selectin expression on hematopoietic and leukemic stem cells

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    Authors
    Sullivan, Con
    Chen, Yaoyu
    Shan, Yi
    Hu, Yiguo
    Peng, Cong
    Zhang, Haojian
    Kong, Linghong
    Li, Shaoguang
    Student Authors
    Haojian Zhang
    UMass Chan Affiliations
    Department of Medicine, Division of Hematology/Oncology
    Document Type
    Journal Article
    Publication Date
    2011-09-23
    Keywords
    Bone Marrow Transplantation; Cell Cycle; Flow Cytometry; Hematopoietic Stem Cells; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Neoplastic Stem Cells; P-Selectin
    Cancer Biology
    Cell and Developmental Biology
    
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    Abstract
    Hematopoiesis is a tightly regulated biological process that relies upon complicated interactions between blood cells and their microenvironment to preserve the homeostatic balance of long-term hematopoietic stem cells (LT-HSCs), short-term HSCs (ST-HSCs), multipotent progenitors (MPPs), and differentiated cells. Adhesion molecules like P-selectin (encoded by the Selp gene) are essential to hematopoiesis, and their dysregulation has been linked to leukemogenesis. Like HSCs, leukemic stem cells (LSCs) depend upon their microenvironments for survival and propagation. P-selectin plays a crucial role in Philadelphia chromosome-positive (Ph(+)) chronic myeloid leukemia (CML). In this paper, we show that cells deficient in P-selectin expression can repopulate the marrow more efficiently than wild type controls. This results from an increase in HSC self-renewal rather than alternative possibilities like increased homing velocity or cell cycle defects. We also show that P-selectin expression on LT-HSCs, but not ST-HSCs and MPPs, increases with aging. In the absence of P-selectin expression, mice at 6 months of age possess increased levels of short-term HSCs and multipotent progenitors. By 11 months of age, there is a shift towards increased levels of long-term HSCs. Recipients of BCR-ABL-transduced bone marrow cells from P-selectin-deficient donors develop a more aggressive CML, with increased percentages of LSCs and progenitors. Taken together, our data reveal that P-selectin expression on HSCs and LSCs has important functional ramifications for both hematopoiesis and leukemogenesis, which is most likely attributable to an intrinsic effect on stem cell self-renewal.
    Source
    PLoS One. 2011;6(10):e26246. doi: 10.1371/journal.pone.0026246. Epub 2011 Oct 24. Link to article on publisher's site
    DOI
    10.1371/journal.pone.0026246
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/33272
    PubMed ID
    22039451
    Related Resources
    Link to Article in PubMed
    ae974a485f413a2113503eed53cd6c53
    10.1371/journal.pone.0026246
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