Conditional c-myb knockout in adult hematopoietic stem cells leads to loss of self-renewal due to impaired proliferation and accelerated differentiation

Hematopoietic stem cells (HSCs) have a unique capacity to undergo self-renewal and multi-lineage differentiation to provide a lifetime supply of mature blood cells. By using conditional knockout technology, we disrupted the c-myb proto-oncogene specifically in adult bone marrow (BM) to demonstrate t...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2009-12, Vol.106 (51), p.21689-21694
Main Authors: Lieu, Yen K, Reddy, E. Premkumar
Format: Article
Language:English
Subjects:
Adults
Animals
Biological Sciences
Blood
Blood cells
Bone marrow
Cell Differentiation
Cell Proliferation
Cells
Erythroid cells
Gene Expression
Hematopoiesis
Hematopoietic stem cells
Hematopoietic Stem Cells - cytology
Hematopoietic Stem Cells - metabolism
Lymphocytes
Mice
Mice, Knockout
myb genes
Proto-Oncogene Proteins c-myb - genetics
Rodents
Stem cells
T lymphocytes
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Summary:Hematopoietic stem cells (HSCs) have a unique capacity to undergo self-renewal and multi-lineage differentiation to provide a lifetime supply of mature blood cells. By using conditional knockout technology, we disrupted the c-myb proto-oncogene specifically in adult bone marrow (BM) to demonstrate that this transcription factor is a regulator of self-renewal and multi-lineage differentiation of adult HSCs. Targeted disruption of the c-myb gene resulted in a critical depletion of the HSC pool. In addition, BM hematopoiesis in adult mice was impaired, resulting in profound reductions of various hematopoietic lineages including neutrophilic, monocytic, B lymphoid, erythroid, and, unexpectedly, megakaryocytic cells. Serial BM transplantation into lethally irradiated recipient mice indicated an essential role for c-myb in the self-renewal process. Furthermore, in vitro functional assays demonstrated that deletion of the c-myb gene leads to a slightly reduced proliferative capacity and an aberrant and accelerated differentiation of HSCs. In addition to long-term HSCs, functional studies also show that c-myb plays a critical role in short-term HSCs and multi-potential progenitors. Collectively, our data indicate a critical role for c-myb in adult BM hematopoiesis and in self-renewal and multi-lineage differentiation of adult HSCs.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0907623106