title: Crebbp haploinsufficiency in mice alters the bone marrow microenvironment, leading to loss of stem cells and excessive myelopoiesis.
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.
authors.affiliation: Greehey Children's Cancer Research Institute, San Antonio, TX, USA.
authors.forename: Stephanie N
authors.initials: SN
authors.lastname: Zimmer
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou
authors.forename: Ting
authors.initials: T
authors.lastname: Zhou
authors.forename: Ziming
authors.initials: Z
authors.lastname: Cheng
authors.forename: Sherry L
authors.initials: SL
authors.lastname: Abboud-Werner
authors.forename: Diane
authors.initials: D
authors.lastname: Horn
authors.forename: Mike
authors.initials: M
authors.lastname: Lecocke
authors.forename: Ruth
authors.initials: R
authors.lastname: White
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Krivtsov
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: David M
authors.initials: DM
authors.lastname: Livingston
authors.forename: Vivienne I
authors.initials: VI
authors.lastname: Rebel
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000502:physiology*; D050882:CREB-Binding Protein / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D005260:Female; D005269:Femur / Q000166:cytology / Q000502:physiology; D057895:Haploinsufficiency / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D006579:Heterozygote; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D038042:Myelopoiesis / Q000502:physiology*; D010010:Osteoclasts / Q000166:cytology / Q000502:physiology; D019089:Stem Cell Factor / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology / Q000502:physiology
chemical_list: D019089:Stem Cell Factor; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse