Abstract
Cell fate determinants influence self-renewal potential of hematopoietic stem cells. Scribble and Llgl1 belong to the Scribble polarity complex and reveal tumor-suppressor function in drosophila. In hematopoietic cells, genetic inactivation of Llgl1 leads to expansion of the stem cell pool and increases self-renewal capacity without conferring malignant transformation. Here we show that genetic inactivation of its putative complex partner Scribble results in functional impairment of hematopoietic stem cells (HSC) over serial transplantation and during stress. Although loss of Scribble deregulates transcriptional downstream effectors involved in stem cell proliferation, cell signaling, and cell motility, these effectors do not overlap with transcriptional targets of Llgl1. Binding partner analysis of Scribble in hematopoietic cells using affinity purification followed by mass spectometry confirms its role in cell signaling and motility but not for binding to polarity modules described in drosophila. Finally, requirement of Scribble for self-renewal capacity also affects leukemia stem cell function. Thus, Scribble is a regulator of adult HSCs, essential for maintenance of HSCs during phases of cell stress.
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Acknowledgements
We thank Ms. S Frey, Mr. VR Thangapandi, and Mrs. A Sammt for technical assistance, and Prof. Dr. Th. Fischer (Magdeburg) for scientific advice during this project. We thank A Fenske, DVM (Magdeburg) for his support with animal care and Dr. R Hartig (Magdeburg) and Dr. Kathrin Schubert (FLI, Jena) for cell sorting. This work was supported by a Research Fellowship Grant of the European Hematology Association (EHA) to FHH, a grant of the German Research Foundation (DFG HE 6233/2-1) and in part by a grant of the Else-Kröner-Fresenius Stiftung (2012-A152) to FHH. Moreover, the project was supported by the Thuringian country programme ProExzellenz (RegenerAging—FSU-I-03/14) of the Thuringian Ministry for Research (TMWWDG). LB was supported by the DFG (Heisenberg-Stipendium BU 1339/3-1).
Author contributions
JM, TMS, BD, NTS, DW, CH, SG, CZ, LB, and TK performed experiments and analyzed data. MN, BH, and TH provided material. TH, TK, DSK, LB, and FHH analyzed data and provided material. TK and FHH wrote the paper.
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Mohr, J., Dash, B.P., Schnoeder, T.M. et al. The cell fate determinant Scribble is required for maintenance of hematopoietic stem cell function. Leukemia 32, 1211–1221 (2018). https://doi.org/10.1038/s41375-018-0025-0
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DOI: https://doi.org/10.1038/s41375-018-0025-0
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