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, Michael Lecocke, Ruth White, Andrei V. Krivtsov, Scott A. Armstrong, Andrew L. Kung, David M. Livingston, and Vivienne I. Rebel


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

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