TY - JOUR
T1 - Rational identification of a Cdc42 inhibitor presents a new regimen for long-term hematopoietic stem cell mobilization
AU - Liu, Wei
AU - Du, Wei
AU - Shang, Xun
AU - Wang, Lei
AU - Evelyn, Chris
AU - Florian, Maria Carolina
AU - A. Ryan, Marnie
AU - Rayes, Ahmad
AU - Zhao, Xueheng
AU - Setchell, Kenneth
AU - Meller, Jarek
AU - Guo, Fukun
AU - Nassar, Nicolas
AU - Geiger, Hartmut
AU - Pang, Qishen
AU - Zheng, Yi
N1 - Publisher Copyright:
© 2018, Springer Nature Limited.
PY - 2019/3/1
Y1 - 2019/3/1
N2 - 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.
AB - 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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U2 - 10.1038/s41375-018-0251-5
DO - 10.1038/s41375-018-0251-5
M3 - Article
C2 - 30254339
AN - SCOPUS:85054034900
SN - 0887-6924
VL - 33
SP - 749
EP - 761
JO - Leukemia
JF - Leukemia
IS - 3
ER -