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Nat Genet. 2014 Mar;46(3):245-52. doi: 10.1038/ng.2889. Epub 2014 Feb 2.

Lis1 regulates asymmetric division in hematopoietic stem cells and in leukemia.

Author information

1
1] Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, California, USA. [2] Sanford Consortium for Regenerative Medicine, La Jolla, California, USA. [3] Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA. [4].
2
1] Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, California, USA. [2] Sanford Consortium for Regenerative Medicine, La Jolla, California, USA. [3].
3
1] Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, California, USA. [2] Sanford Consortium for Regenerative Medicine, La Jolla, California, USA.
4
Division of Cell Therapy, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
5
1] Department of Pathology, University of California San Diego School of Medicine, La Jolla, California, USA. [2] Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, California, USA.
6
1] Department of Haematology, Singapore General Hospital, Singapore. [2] Cancer and Stem Cell Biology Program, Duke-National University of Singapore Graduate Medical School, Singapore.
7
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
8
Department of Medicine, University of California San Diego School of Medicine, La Jolla, California, USA.
9
1] Department of Medicine, University of California San Diego School of Medicine, La Jolla, California, USA. [2] Computational Science Research Center and Biomedical Informatics Research Center, San Diego State University, San Diego, California, USA.
10
1] Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, California, USA. [2] Sanford Consortium for Regenerative Medicine, La Jolla, California, USA. [3] Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA. [4] Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, California, USA.

Abstract

Cell fate can be controlled through asymmetric division and segregation of protein determinants, but the regulation of this process in the hematopoietic system is poorly understood. Here we show that the dynein-binding protein Lis1 is critically required for hematopoietic stem cell function and leukemogenesis. Conditional deletion of Lis1 (also known as Pafah1b1) in the hematopoietic system led to a severe bloodless phenotype, depletion of the stem cell pool and embryonic lethality. Further, real-time imaging revealed that loss of Lis1 caused defects in spindle positioning and inheritance of cell fate determinants, triggering accelerated differentiation. Finally, deletion of Lis1 blocked the propagation of myeloid leukemia and led to a marked improvement in survival, suggesting that Lis1 is also required for oncogenic growth. These data identify a key role for Lis1 in hematopoietic stem cells and mark its directed control of asymmetric division as a critical regulator of normal and malignant hematopoietic development.

PMID:
24487275
PMCID:
PMC4267534
DOI:
10.1038/ng.2889
[Indexed for MEDLINE]
Free PMC Article
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