title: Rb regulates interactions between hematopoietic stem cells and their bone marrow microenvironment.
abstract: Hematopoiesis is maintained by stem cells (HSCs) that undergo fate decisions by integrating intrinsic and extrinsic signals, with the latter derived from the bone marrow (BM) microenvironment. Cell-cycle regulation can modulate stem cell fate, but it is unknown whether this represents an intrinsic or extrinsic effector of fate decisions. We have investigated the role of the retinoblastoma protein (RB), a central regulator of the cell cycle, in hematopoiesis. Widespread inactivation of RB in the murine hematopoietic system resulted in profound myeloproliferation. HSCs were lost from the BM due to mobilization to extramedullary sites and differentiation. This phenotype was not intrinsic to HSCs, but, rather, was the consequence of an RB-dependent interaction between myeloid-derived cells and the microenvironment. These findings demonstrate that myeloproliferation may result from perturbed interactions between hematopoietic cells and the niche. Therefore, RB extrinsically regulates HSCs by maintaining the capacity of the BM to support normal hematopoiesis and HSCs.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Division of Hematology/Oncology and Stem Cell Program, Children's Hospital Boston, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Carl R
authors.initials: CR
authors.lastname: Walkley
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Shea
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Sims
authors.forename: Louise E
authors.initials: LE
authors.lastname: Purton
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism*; D001854:Bone Marrow Cells; D002453:Cell Cycle; D002454:Cell Differentiation; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009196:Myeloproliferative Disorders / Q000378:metabolism; D010641:Phenotype; D016160:Retinoblastoma Protein / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology; D013997:Time Factors
chemical_list: D016160:Retinoblastoma Protein