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 language | English (US) |
|---|---|
| Pages (from-to) | 69-79 |
| Number of pages | 11 |
| Journal | Blood |
| Volume | 118 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jul 7 2011 |
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ASJC Scopus subject areas
- Hematology
- Biochemistry
- Cell Biology
- Immunology
Cite this
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 journal › Article
}
TY - JOUR
T1 - Crebbp haploinsufficiency in mice alters the bone marrow microenvironment, leading to loss of stem cells and excessive myelopoiesis
AU - Zimmer, Stephanie N.
AU - Zhou, Qing
AU - Zhou, Ting
AU - Cheng, Ziming
AU - Abboud-Werner, Sherry L.
AU - Horn, Diane
AU - Lecocke, Mike
AU - White, Ruth
AU - Krivtsov, Andrei V.
AU - Armstrong, Scott A.
AU - Kung, Andrew L.
AU - Livingston, David M.
AU - Rebel, Vivienne I.
PY - 2011/7/7
Y1 - 2011/7/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79960139808&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79960139808&partnerID=8YFLogxK
U2 - 10.1182/blood-2010-09-307942
DO - 10.1182/blood-2010-09-307942
M3 - Article
C2 - 21555743
AN - SCOPUS:79960139808
VL - 118
SP - 69
EP - 79
JO - Blood
JF - Blood
SN - 0006-4971
IS - 1
ER -