Rational identification of a Cdc42 inhibitor presents a new regimen for long-term hematopoietic stem cell mobilization.
Animals
Benzylamines
Bone Marrow
/ drug effects
Cell Movement
/ drug effects
Cyclams
Cytokines
/ metabolism
Granulocyte Colony-Stimulating Factor
/ metabolism
Hematopoietic Stem Cell Mobilization
/ methods
Hematopoietic Stem Cell Transplantation
/ methods
Hematopoietic Stem Cells
/ drug effects
Heterocyclic Compounds
/ pharmacology
Mice
Mice, Inbred C57BL
Small Molecule Libraries
/ pharmacology
Stem Cells
/ drug effects
cdc42 GTP-Binding Protein
/ antagonists & inhibitors
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
17
06
2018
accepted:
14
08
2018
revised:
19
07
2018
pubmed:
27
9
2018
medline:
20
7
2019
entrez:
27
9
2018
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30254339
doi: 10.1038/s41375-018-0251-5
pii: 10.1038/s41375-018-0251-5
pmc: PMC6414073
mid: NIHMS1005215
doi:
Substances chimiques
Benzylamines
0
Cdc42 protein, mouse
0
Cyclams
0
Cytokines
0
Heterocyclic Compounds
0
Small Molecule Libraries
0
Granulocyte Colony-Stimulating Factor
143011-72-7
cdc42 GTP-Binding Protein
EC 3.6.5.2
plerixafor
S915P5499N
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
749-761Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK104814
Pays : United States
Organisme : NIGMS NIH HHS
ID : U54 GM104942
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA193350
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL085362
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA204895
Pays : United States
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