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Leukemia. 2014 Sep;28(9):1844-50. doi: 10.1038/leu.2014.73. Epub 2014 Feb 18.

Haploinsufficiency of Sf3b1 leads to compromised stem cell function but not to myelodysplasia.

Author information

1
Departments of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
2
Division of Stem Cell Therapy, Center for Stem Cell Biology and Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
3
Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
4
1] Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan [2] Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
5
Laboratory for Developmental Genetics, RIKEN Research Center for Integrative Medical Sciences, Yokohama, Japan.

Abstract

SF3B1 is a core component of the mRNA splicing machinery and frequently mutated in myeloid neoplasms with myelodysplasia, particularly in those characterized by the presence of increased ring sideroblasts. Deregulated RNA splicing is implicated in the pathogenesis of SF3B1-mutated neoplasms, but the exact mechanism by which the SF3B1 mutation is associated with myelodysplasia and the increased ring sideroblasts formation is still unknown. We investigated the functional role of SF3B1 in normal hematopoiesis utilizing Sf3b1 heterozygous-deficient mice. Sf3b1(+/-) mice had a significantly reduced number of hematopoietic stem cells (CD34(-)cKit(+)ScaI(+)Lin(-) cells or CD34(-)KSL cells) compared with Sf3b1(+/+) mice, but hematopoiesis was grossly normal in Sf3b1(+/-) mice. When transplanted competitively with Sf3b1(+/+) bone marrow cells, Sf3b1(+/-) stem cells showed compromised reconstitution capacity in lethally irradiated mice. There was no increase in the number of ring sideroblasts or evidence of myeloid dysplasia in Sf3b1(+/-) mice. These data suggest that SF3B1 plays an important role in the regulation of hematopoietic stem cells, whereas SF3B1 haploinsufficiency itself is not associated with the myelodysplastic syndrome phenotype with ring sideroblasts.

PMID:
24535406
DOI:
10.1038/leu.2014.73
[Indexed for MEDLINE]

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