Page 141 - Haematologica Vol. 109 - July 2024

ARTICLE - Ppm1b regulates HSC homeostasis
Z. Lu et al.
findings were not invalidated by the serial transplant or CRU data, suggesting that there might be two at least partially in- dependent stages of PPM1B activity. Consequently, the impact of Ppm1b deletion on B-cell development may take place at the level of stem and progenitor cells, even in populations lacking an apparent inclination for lineage differentiation. In summary, our study identified an essential role for Ppm1b in HSC homeostasis via Wnt/b-catenin signaling. Our findings may provide novel insights into the understanding of HSC self-renewal and B-cell development, and also offer clues for the pathogenesis of their related hematologic malignancies.
Disclosures
No conflicts of interest to disclose.
Contributions
BZ designed and guided research. ZL, YH, GX, XL and YL per- formed the experiments. ZL, YH, ZL, CZ and BZ analyzed the data. ZL and BZ wrote the original draft. ZL, YS, CZ and BZ reviewed and edited the manuscript. All authors have read and agreed to the published version of the manuscript.
Acknowledgments
We thank the Translational Medicine Core Facility and Core
References
1. Eaves CJ. Hematopoietic stem cells: concepts, definitions, and the new reality. Blood. 2015;125(17):2605-2613.
2. Sieweke MH, Allen JE. Beyond stem cells: self-renewal of differentiated macrophages. Science. 2013;342(6161):1242974.
3. de Haan G, Lazare SS. Aging of hematopoietic stem cells. Blood. 2018;131(5):479-487.
4. Verovskaya EV, Dellorusso PV, Passegue E. Losing sense of self and surroundings: hematopoietic stem cell aging and leukemic transformation. Trends Mol Med. 2019;25(6):494-515.
5. Wilkinson AC, Igarashi KJ, Nakauchi H. Haematopoietic stem cell self-renewal in vivo and ex vivo. Nat Rev Genet. 2020;21(9):541-554.
6. Humphrey SJ, James DE, Mann M. Protein phosphorylation: a major switch mechanism for metabolic regulation. Trends Endocrinol Metab. 2015;26(12):676-687.
7. Kamada R. Metal-dependent Ser/Thr protein phosphatase PPM family: evolution, structures, diseases and inhibitors. Pharmacol Ther. 2020;215:107622.
8. Adolfsson J, Mansson R, Buza-Vidas N, et al. Identification of Flt3+ lympho-myeloid stem cells lacking erythro- megakaryocytic potential a revised road map for adult blood lineage commitment. Cell. 2005;121(2):295-306.
9. Okada S, Nakauchi H, Nagayoshi K, Nishikawa S, Miura Y, Suda T. In vivo and in vitro stem cell function of c-kit- and Sca-1-positive murine hematopoietic cells. Blood. 1992;80(12):3044-3050.
10. Ito K, Turcotte R, Cui JH, et al. Self-renewal of a purified Tie2(+) hematopoietic stem cell population relies on mitochondrial clearance. Science. 2016;354(6316):1156-1160.
11. Holmes T, O’Brien TA, Knight R, et al. Glycogen synthase kinase-3 beta inhibition preserves hematopoietic stem cell activity and inhibits leukemic cell growth. Stem Cells.
Facility of the School of Basic Medical Sciences of Shandong University for consultation and instrument availability that supported this work. This work was supported by grants from the National Natural Science Foundation of China (81874294, 32300957), Taishan Scholars Program (TSQN201812015) and the key Program of Natural Science Foundation of Shandong Province (ZR2022LSW027), Qilu Young Scholars Program (to BZ), and the Multidisciplinary Research and Innovation Team of Young Scholars (2020QNQT007) of Shandong University. This work was also supported by the program for Innovative Research Team at University of the Ministry of Education of China (IRT_17R68), the academic promotion program of Shandong First Medical University (No.2019LJ003), the Natural Science Foundation of Shandong Province (ZR2023QH427), and the Innovation Team of Shandong Higher School Youth Innovation Technology Program (2022KJ197).
Data-sharing statement
Supporting data are available in the Online Supplementary Appendix. RNA sequencing data that support the findings of this study have been deposited in NCBI SRA under accession number GSE23774. The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
2008;26(5):1288-1297.
12. Li CZ, Wu BH, Li YS, et al. Loss of sphingosine kinase 2
promotes the expansion of hematopoietic stem cells by
improving their metabolic fitness. Blood. 2022;140(15):1686-1701. 13. Zhang XF, Wang JF, Matczak E, Proper J, Groopman JE. Janus
kinase 2 is involved in stromal cell-derived factor-1 alpha- induced tyrosine phosphorylation of focal adhesion proteins and migration of hematopoietic progenitor cells. Blood. 2001;97(11):3342-3348.
14. Chan G, Cheung LS, Yang WT, et al. Essential role for Ptpn11 in survival of hematopoietic stem and progenitor cells. Blood. 2011;117(16):4253-4261.
15. Ni F, Yu WM, Wang X, et al. Ptpn21 controls hematopoietic stem cell homeostasis and biomechanics. Cell Stem Cell. 2019;24(4):608-620
16. Zhang J, Vakhrusheva O, Bandi SR, et al. The phosphatases STS1 and STS2 regulate hematopoietic stem and progenitor cell fitness. Stem Cell Reports. 2015;5(4):633-646.
17. Liu XY, Zhang FF, Zhang YP, et al. PPM1K regulates hematopoiesis and leukemogenesis through CDC20-mediated ubiquitination of MEIS1 and p21. Cell Rep. 2018;23(5):1461-1475.
18. Chen ZY, Yi WW, Morita YH, et al. Wip1 deficiency impairs haematopoietic stem cell function via p53 and mTORC1 pathways. Nat Commun. 2015;6:6808.
19. Marley AE, Kline A, Crabtree G, Sullivan JE, Beri RK. The cloning expression and tissue distribution of human PP2C beta. FEBS Lett. 1998;431(1):121-124.
20. Li ZY, Chen RY, Li YX, et al. A comprehensive overview of PPM1B: from biological functions to diseases. Eur J Pharmacol. 2023;947:175633.
21. Skottman H, Mikkola M, Lundin K, et al. Gene expression
Haematologica | 109 July 2024
2155