functional ramifications for the loss of p-selectin expression on hematopoietic and leukemic stem cells造血功能影响的损失p-selectin表情和白血病干细胞.pdfVIP

Functional Ramifications for the Loss of P-Selectin Expression on Hematopoietic and Leukemic Stem Cells 1,3. 2,3.¤ 2 3,4 2,3 2,3 Con Sullivan , Yaoyu Chen , Yi Shan , Yiguo Hu , Cong Peng , Haojian Zhang , Linghong Kong3, Shaoguang Li2,3* 1 Maine Institute for Human Genetics and Health, Bangor, Maine, United States of America, 2 Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America, 3 The Jackson Laboratory, Bar Harbor, Maine, United States of America, 4 Dana Farber Cancer Institute, Boston, Massachusetts, United States of America 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