Blood Journal
Leading the way in experimental and clinical research in hematology

Crebbp haploinsufficiency in mice alters the bone marrow microenvironment, leading to loss of stem cells and excessive myelopoiesis

  1. Stephanie N. Zimmer1,2,
  2. Qing Zhou1,
  3. Ting Zhou1,2,
  4. Ziming Cheng1,
  5. Sherry L. Abboud-Werner3,
  6. Diane Horn3,
  7. Mike Lecocke4,5,
  8. Ruth White6,
  9. Andrei V. Krivtsov7,
  10. Scott A. Armstrong7,
  11. Andrew L. Kung8,
  12. David M. Livingston9, and
  13. Vivienne I. Rebel1,2
  1. 1Greehey Children's Cancer Research Institute,
  2. 2Department of Cellular and Structural Biology,
  3. 3Department of Pathology, and
  4. 4Department of Epidemiology & Biostatistics, University of Texas Health Science Center at San Antonio, San Antonio, TX;
  5. 5Department of Mathematics, St. Mary's University, San Antonio, TX;
  6. 6Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, OR;
  7. 7Division of Hematology/Oncology, Children's Hospital, Harvard Medical School, Boston, MA; and
  8. Departments of 8Pediatric Oncology and
  9. 9Cancer Biology, Dana-Farber Cancer Institute, Boston, MA

Abstract

CREB-binding protein (CREBBP) is important for the cell-autonomous regulation of hematopoiesis, including the stem cell compartment. In the present study, we show that CREBBP plays an equally pivotal role in microenvironment-mediated regulation of hematopoiesis. We found that the BM microenvironment of Crebbp+/− mice was unable to properly maintain the immature stem cell and progenitor cell pools. Instead, it stimulates myeloid differentiation, which progresses into a myeloproliferation phenotype. Alterations in the BM microenvironment resulting from haploinsufficiency of Crebbp included a marked decrease in trabecular bone that was predominantly caused by increased osteoclastogenesis. Although CFU-fibroblast (CFU-F) and total osteoblast numbers were decreased, the bone formation rate was similar to that found in wild-type mice. At the molecular level, we found that the known hematopoietic modulators matrix metallopeptidase-9 (MMP9) and kit ligand (KITL) were decreased with heterozygous levels of Crebbp. Lastly, potentially important regulatory proteins, endothelial cell adhesion molecule 1 (ESAM1) and cadherin 5 (CDH5), were increased on Crebbp+/− endothelial cells. Our findings reveal that a full dose of Crebbp is essential in the BM microenvironment to maintain proper hematopoiesis and to prevent excessive myeloproliferation.

  • Submitted September 17, 2010.
  • Accepted April 19, 2011.
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