title: Bcl11a Deficiency Leads to Hematopoietic Stem Cell Defects with an Aging-like Phenotype.
abstract: B cell CLL/lymphoma 11A (BCL11A) is a transcription factor and regulator of hemoglobin switching that has emerged as a promising therapeutic target for sickle cell disease and thalassemia. In the hematopoietic system, BCL11A is required for B lymphopoiesis, yet its role in other hematopoietic cells, especially hematopoietic stem cells (HSCs) remains elusive. The extensive expression of BCL11A in hematopoiesis implicates context-dependent roles, highlighting the importance of fully characterizing its function as part of ongoing efforts for stem cell therapy and regenerative medicine. Here, we demonstrate that BCL11A is indispensable for normal HSC function. Bcl11a deficiency results in HSC defects, typically observed in the aging hematopoietic system. We find that downregulation of cyclin-dependent kinase 6 (Cdk6), and the ensuing cell-cycle delay, correlate with HSC dysfunction. Our studies define a mechanism for BCL11A in regulation of HSC function and have important implications for the design of therapeutic approaches to targeting BCL11A.
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Stem Cell Institute, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sidinh
authors.initials: S
authors.lastname: Luc
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Stem Cell Institute, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA.
authors.forename: Jialiang
authors.initials: J
authors.lastname: Huang
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Stem Cell Institute, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: McEldoon
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Stem Cell Institute, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ece
authors.initials: E
authors.lastname: Somuncular
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Stem Cell Institute, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Stem Cell Institute, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Claire
authors.initials: C
authors.lastname: Rhodes
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Stem Cell Institute, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Shahan
authors.initials: S
authors.lastname: Mamoor
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Stem Cell Institute, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Serena
authors.initials: S
authors.lastname: Hou
authors.affiliation: Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: jian.xu@utsouthwestern.edu.
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Stem Cell Institute, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: stuart_orkin@dfci.harvard.edu.
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D016922:Cellular Senescence / Q000235:genetics*; D051361:Cyclin-Dependent Kinase 6 / Q000096:biosynthesis; D004268:DNA-Binding Proteins; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D012097:Repressor Proteins
chemical_list: C407733:Bcl11a protein, mouse; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; C495912:Cdk6 protein, mouse; D051361:Cyclin-Dependent Kinase 6