title: Functional ramifications for the loss of P-selectin expression on hematopoietic and leukemic stem cells.
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.
authors: Maine Institute for Human Genetics and Health, Bangor, Maine, United States of America.
authors: Con
authors: C
authors: Sullivan
authors: Yaoyu
authors: Y
authors: Chen
authors: Yi
authors: Y
authors: Shan
authors: Yiguo
authors: Y
authors: Hu
authors: Cong
authors: C
authors: Peng
authors: Haojian
authors: H
authors: Zhang
authors: Linghong
authors: L
authors: Kong
authors: Shaoguang
authors: S
authors: Li
mesh_terms: D016026:Bone Marrow Transplantation; D002453:Cell Cycle; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology* / Q000601:surgery; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D019007:P-Selectin / Q000378:metabolism*
chemical_list: D019007:P-Selectin