title: The Phosphatases STS1 and STS2 Regulate Hematopoietic Stem and Progenitor Cell Fitness.
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.
authors.affiliation: Department of Medicine, Hematology/Oncology, Goethe University, 60590 Frankfurt, Germany; German Cancer Consortium, 69120 Heidelberg, Germany; German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Hematology/Oncology, Goethe University, 60590 Frankfurt, Germany.
authors.forename: Olesya
authors.initials: O
authors.lastname: Vakhrusheva
authors.affiliation: Department of Medicine, Hematology/Oncology, Goethe University, 60590 Frankfurt, Germany.
authors.forename: Srinivasa Rao
authors.initials: SR
authors.lastname: Bandi
authors.affiliation: Department of Medicine, Hematology/Oncology, Goethe University, 60590 Frankfurt, Germany; German Cancer Consortium, 69120 Heidelberg, Germany; German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Özlem
authors.initials: Ö
authors.lastname: Demirel
authors.affiliation: Division of Translational Cancer Research and Lund Stem Cell Center, Lund University, Medicon Village, 22363 Lund, Sweden.
authors.forename: Julhash U
authors.initials: JU
authors.lastname: Kazi
authors.affiliation: Department of Medicine, Hematology/Oncology, Goethe University, 60590 Frankfurt, Germany.
authors.forename: Ramona Gomes
authors.initials: RG
authors.lastname: Fernandes
authors.affiliation: Department of Medicine, Hematology/Oncology, Goethe University, 60590 Frankfurt, Germany; German Cancer Consortium, 69120 Heidelberg, Germany; German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Jakobi
authors.affiliation: Department of Medicine, Hematology/Oncology, Goethe University, 60590 Frankfurt, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Eichler
authors.affiliation: Division of Translational Cancer Research and Lund Stem Cell Center, Lund University, Medicon Village, 22363 Lund, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Rönnstrand
authors.affiliation: Department of Medicine, Hematology/Oncology, Goethe University, 60590 Frankfurt, Germany; German Cancer Consortium, 69120 Heidelberg, Germany; German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Rieger
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Nick
authors.initials: N
authors.lastname: Carpino
authors.affiliation: Department of Medicine, Hematology/Oncology, Goethe University, 60590 Frankfurt, Germany; German Cancer Consortium, 69120 Heidelberg, Germany; German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Hubert
authors.initials: H
authors.lastname: Serve
authors.affiliation: 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.
authors.forename: Christian H
authors.initials: CH
authors.lastname: Brandts
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism*
chemical_list: D011948:Receptors, Antigen, T-Cell; C482177:Sts-2 protein, mouse; C497971:Flt3 protein, mouse; D019009:Proto-Oncogene Proteins c-kit; D051941:fms-Like Tyrosine Kinase 3; D017027:Protein Tyrosine Phosphatases; C553497:TULA-2 protein, mouse