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Stem Cell Reports. 2015 Oct 13;5(4):633-46. doi: 10.1016/j.stemcr.2015.08.006. Epub 2015 Sep 10.

The Phosphatases STS1 and STS2 Regulate Hematopoietic Stem and Progenitor Cell Fitness.

Author information

1
Department of Medicine, Hematology/Oncology, Goethe University, 60590 Frankfurt, Germany; German Cancer Consortium, 69120 Heidelberg, Germany; German Cancer Research Center, 69120 Heidelberg, Germany.
2
Department of Medicine, Hematology/Oncology, Goethe University, 60590 Frankfurt, Germany.
3
Division of Translational Cancer Research and Lund Stem Cell Center, Lund University, Medicon Village, 22363 Lund, Sweden.
4
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794, USA.
5
Department of Medicine, Hematology/Oncology, Goethe University, 60590 Frankfurt, Germany; German Cancer Consortium, 69120 Heidelberg, Germany; German Cancer Research Center, 69120 Heidelberg, Germany. Electronic address: brandts@em.uni-frankfurt.de.

Abstract

FLT3 and c-KIT are crucial regulators of hematopoietic stem and progenitor cells. We investigated the role of STS1 and STS2 on FLT3 and c-KIT phosphorylation, activity, and function in normal and stress-induced hematopoiesis. STS1/STS2-deficient mice show a profound expansion of multipotent progenitor and lymphoid primed multipotent progenitor cells with elevated colony-forming capacity. Although long-term hematopoietic stem cells are not increased in numbers, lack of STS1 and STS2 significantly promotes long-term repopulation activity, demonstrating a pivotal role of STS1/STS2 in regulating hematopoietic stem and progenitor cell fitness. Biochemical analysis identified STS1/STS2 as direct phosphatases of FLT3 and c-KIT. Loss of STS1/STS2 induces hyperphosphorylation of FLT3, enhances AKT signaling, and confers a strong proliferative advantage. Therefore, our study reveals that STS1 and STS2 may serve as novel pharmaceutical targets to improve hematopoietic recovery after bone marrow transplantation.

PMID:
26365512
PMCID:
PMC4624938
DOI:
10.1016/j.stemcr.2015.08.006
[Indexed for MEDLINE]
Free PMC Article

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