Department of Medicine, Hematology/Oncology, Goethe University, 60590 Frankfurt, Germany; German Cancer Consortium, 69120 Heidelberg, Germany; German Cancer Research Center, 69120 Heidelberg, Germany.
Department of Medicine, Hematology/Oncology, Goethe University, 60590 Frankfurt, Germany.
Stem Cell Reports. 2015 Oct 13;5(4):633-46. doi: 10.1016/j.stemcr.2015.08.006. Epub 2015 Sep 10.
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.
FLT3 和 c-KIT 是造血干细胞和祖细胞的关键调节因子。我们研究了 STS1 和 STS2 在正常和应激诱导造血中对 FLT3 和 c-KIT 磷酸化、活性和功能的作用。STS1/STS2 缺陷小鼠显示出多能祖细胞和淋巴样前体细胞的显著扩增,具有更高的集落形成能力。尽管长期造血干细胞数量没有增加,但缺乏 STS1 和 STS2 显著促进长期重殖活性,表明 STS1/STS2 在调节造血干细胞和祖细胞适应性方面起着关键作用。生化分析确定 STS1/STS2 是 FLT3 和 c-KIT 的直接磷酸酶。STS1/STS2 的缺失导致 FLT3 的过度磷酸化,增强 AKT 信号转导,并赋予强大的增殖优势。因此,我们的研究表明,STS1 和 STS2 可能成为改善骨髓移植后造血恢复的新型药物靶点。