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

Stephanie N. Zimmer, Qing Zhou, Ting Zhou, Ziming Cheng, Sherry L. Abboud-Werner, Diane Horn, Mike Lecocke, Ruth White, Andrei V. Krivtsov, Scott A. Armstrong, Andrew L. Kung, David M. Livingston, Vivienne I. Rebel

Research output: Contribution to journalArticle

20 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)69-79
Number of pages11
JournalBlood
Volume118
Issue number1
DOIs
StatePublished - Jul 7 2011

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CREB-Binding Protein
Myelopoiesis
Haploinsufficiency
Endothelial cells
Hematopoiesis
Stem cells
Bone
Stem Cells
Bone Marrow
Osteogenesis
Stem Cell Factor
Osteoblasts
Cell Adhesion Molecules
Metalloproteases
Fibroblasts
Endothelial Cells
Modulators
Phenotype
Proteins
cadherin 5

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Zimmer, S. N., Zhou, Q., Zhou, T., Cheng, Z., Abboud-Werner, S. L., Horn, D., ... Rebel, V. I. (2011). Crebbp haploinsufficiency in mice alters the bone marrow microenvironment, leading to loss of stem cells and excessive myelopoiesis. Blood, 118(1), 69-79. https://doi.org/10.1182/blood-2010-09-307942

Crebbp haploinsufficiency in mice alters the bone marrow microenvironment, leading to loss of stem cells and excessive myelopoiesis. / Zimmer, Stephanie N.; Zhou, Qing; Zhou, Ting; Cheng, Ziming; Abboud-Werner, Sherry L.; Horn, Diane; Lecocke, Mike; White, Ruth; Krivtsov, Andrei V.; Armstrong, Scott A.; Kung, Andrew L.; Livingston, David M.; Rebel, Vivienne I.

In: Blood, Vol. 118, No. 1, 07.07.2011, p. 69-79.

Research output: Contribution to journalArticle

Zimmer, SN, Zhou, Q, Zhou, T, Cheng, Z, Abboud-Werner, SL, Horn, D, Lecocke, M, White, R, Krivtsov, AV, Armstrong, SA, Kung, AL, Livingston, DM & Rebel, VI 2011, 'Crebbp haploinsufficiency in mice alters the bone marrow microenvironment, leading to loss of stem cells and excessive myelopoiesis', Blood, vol. 118, no. 1, pp. 69-79. https://doi.org/10.1182/blood-2010-09-307942
Zimmer, Stephanie N. ; Zhou, Qing ; Zhou, Ting ; Cheng, Ziming ; Abboud-Werner, Sherry L. ; Horn, Diane ; Lecocke, Mike ; White, Ruth ; Krivtsov, Andrei V. ; Armstrong, Scott A. ; Kung, Andrew L. ; Livingston, David M. ; Rebel, Vivienne I. / Crebbp haploinsufficiency in mice alters the bone marrow microenvironment, leading to loss of stem cells and excessive myelopoiesis. In: Blood. 2011 ; Vol. 118, No. 1. pp. 69-79.
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