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Stem cell transplantation

Rational identification of a Cdc42 inhibitor presents a new regimen for long-term hematopoietic stem cell mobilization

Leukemiavolume 33pages749761 (2019) | Download Citation


Mobilization of hematopoietic stem cells (HSCs) from bone marrow (BM) to peripheral blood (PB) by cytokine granulocyte colony-stimulating factor (G-CSF) or the chemical antagonist of CXCR4, AMD3100, is important in the treatment of blood diseases. Due to clinical conditions of each application, there is a need for continued improvement of HSC mobilization regimens. Previous studies have shown that genetic ablation of the Rho GTPase Cdc42 in HSCs results in their mobilization without affecting survival. Here we rationally identified a Cdc42 activity-specific inhibitor (CASIN) that can bind to Cdc42 with submicromolar affinity and competitively interfere with guanine nucleotide exchange activity. CASIN inhibits intracellular Cdc42 activity specifically and transiently to induce murine hematopoietic stem/progenitor cell egress from the BM by suppressing actin polymerization, adhesion, and directional migration of stem/progenitor cells, conferring Cdc42 knockout phenotypes. We further show that, although, CASIN administration to mice mobilizes similar number of phenotypic HSCs as AMD3100, it produces HSCs with better long-term reconstitution potential than that by AMD3100. Our work validates a specific small molecule inhibitor for Cdc42, and demonstrates that signaling molecules downstream of cytokines and chemokines, such as Cdc42, constitute a useful target for long-term stem cell mobilization.

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We thank James F. Johnson, Victoria Summey, and Jeff Bailey for assistance in xenograft experiments. This work was supported in part by the NIH grants R01 CA193350, DK104814, CA204895, and HL085362.

Author contributions

W.L. and W.D. designed and performed the research, analyzed the data, and wrote the paper. X.S., L.W., C.E., M.C.F., M.A.R., A.R., X.Z., K.S., F.G., performed some of the experiments. N.N., J.M., H.G., and Q.P. designed the research. Y.Z. designed the research, analyzed the data, and wrote the paper.

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Author notes

  1. These authors contributed equally: Wei Liu, Wei Du


  1. Cancer and Blood Diseases Institute, University of Cincinnati, Cincinnati, OH, 45229, USA

    • Wei Liu
    • , Xun Shang
    • , Lei Wang
    • , Chris Evelyn
    • , Marnie A. Ryan
    • , Ahmad Rayes
    • , Fukun Guo
    • , Nicolas Nassar
    • , Hartmut Geiger
    • , Qishen Pang
    •  & Yi Zheng
  2. Department of Pharmaceutical Sciences, West Virginia University School of Pharmacy, Morgantown, WV, 26506, USA

    • Wei Du
  3. Institute of Molecular Medicine, University of Ulm, Ulm, Germany

    • Maria Carolina Florian
    •  & Hartmut Geiger
  4. Division of Pathology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 45229, USA

    • Xueheng Zhao
    •  & Kenneth Setchell
  5. Division of Biomedical Informatics, Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH, 45229, USA

    • Jarek Meller


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The authors declare that they have no conflict of interest.

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Correspondence to Yi Zheng.

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