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 metallo-

Revisiting the case for genetically engineered mouse models in human myelodysplastic syndrome research

“…30 The hematologic syndrome observed in naïve Crebbp 1/2 mice was therefore classified as an MDS/MPN overlap disease. 40,42,46,47 The BM microenvironment contributes to the myeloproliferative component of the hematologic disease observed in Crebbp 1/2 mice, in part through the altered production levels of KITL and MMP9. 47 In the absence of the proliferative stimulus of the Crebbp In the PB, abnormal erythropoiesis manifested itself by basophilic stippling (Figure 3Ei) and anisocytosis, as well as poikilocytosis (ie, the presence of abnormally shaped red cells such as target cells and teardrop cells; Figure 3F).…”

The Transcriptional Coactivator Cbp Regulates Self-Renewal and Differentiation in Adult Hematopoietic Stem Cells

“…Moreover, it was shown recently that the Cbp ϩ/Ϫ microenvironment fails to maintain normal HSC function (53). To examine if deletion of Cbp in the HSC microenvironment during homeostasis affects the reconstitution abilities of wt HSCs, we transplanted wt whole BM cells (CD45.1) into lethally irradiated Cbp wt or Cbp Mx recipients (CD45.2) 4 weeks after poly(I) ⅐ poly(C) treatment.…”

“…Although studies of adult mice have demonstrated the importance of Cbp and p300 for B-and T-cell development (19,46), no studies have demonstrated the consequences of Cbp deficiency in normal adult HSC maintenance and function. A recent study also suggested a potential role for Cbp in the hematopoietic microenvironment (53). Despite all these studies, the cellular mechanisms as well as the hematopoietic transcriptional network by which Cbp regulates hematopoiesis and adult HSC function have not been addressed.…”

Role of CREB Protein Family Members in Human Haematological Malignancies

“…Furthermore, it has been reported that CREBBP(+/-) mice have reduced bone volume due to increased osteoclastogenesis. A concomitant reduction in CFU-fibroblasts (CFU-Fs) and osteoblasts per tissue area was also identified and likely contributes to fewer HSC niches [41]. Thus, all these findings reveal the importance of CBP in the development and function of the BM microenvironment and underscore the multiple levels at which this protein acts to regulate haematopoiesis.…”

“…Mutations of CREBBP in the germline have been associated to the Rubinstein-Taybi syndrome (RTS), an autosomal dominant disease characterized by mental retardation, skeletal abnormalities and a high propensity to develop cancer, including leukaemia [36]. Similarly, CREBBP(+/-) mice show abnormalities in bone, haematopoietic tissues and neural tissues and an increased tendency to develop haematological malignancies with age [41]. In earlier studies, in CREBBP(+/-) HSCs (haematopoietic stem cells) a number of cell-intrinsic defects have been described, including diminished HSC self-renewal and excessive myeloid differentiation [42].…”