TY - JOUR
T1 - Bcl11a Deficiency Leads to Hematopoietic Stem Cell Defects with an Aging-like Phenotype
AU - Luc, Sidinh
AU - Huang, Jialiang
AU - McEldoon, Jennifer L.
AU - Somuncular, Ece
AU - Li, Dan
AU - Rhodes, Claire
AU - Mamoor, Shahan
AU - Hou, Serena
AU - Xu, Jian
AU - Orkin, Stuart H.
N1 - Funding Information:
We thank Dr. H. Tucker (University of Texas at Austin) for providing the conditional Bcl11a mouse strain, Dr. N. Iscove (Ontario Cancer Institute, University Health Network) for providing the C57BL/6J-Ly5.1-Kit W-41/W-41 -Gpi a/a mice, and Z. Herbert and L. Grimmett from the Molecular Biology Core Facilities at the Dana-Farber Cancer Institute for processing microarray samples. We are grateful to Dr. D. Bauer for critical comments. S.L. is supported by a fellow award from the Leukemia & Lymphoma Society. J.X. is supported by NIH/NIDDK grants (K01DK093543 and R03DK101665) and a CPRIT New Investigator award (RR140025). S.H.O. is an investigator of the Howard Hughes Medical Institute (HHMI) and supported by P30DK049216 and R01HL032259.
Publisher Copyright:
© 2016 The Authors
PY - 2016/9/20
Y1 - 2016/9/20
N2 - 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.
AB - 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.
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U2 - 10.1016/j.celrep.2016.08.064
DO - 10.1016/j.celrep.2016.08.064
M3 - Article
C2 - 27653684
AN - SCOPUS:84989884580
SN - 2211-1247
VL - 16
SP - 3181
EP - 3194
JO - Cell Reports
JF - Cell Reports
IS - 12
ER -