PMID- 26320102
OWN - NLM
STAT- MEDLINE
DCOM- 20160119
LR  - 20210202
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Linking)
VI  - 126
IP  - 15
DP  - 2015 Oct 8
TI  - CD9, a key actor in the dissemination of lymphoblastic leukemia, modulating 
      CXCR4-mediated migration via RAC1 signaling.
PG  - 1802-12
LID - 10.1182/blood-2015-02-628560 [doi]
AB  - CD9, a member of the tetraspanin family, has been implicated in hematopoietic and 
      leukemic stem cell homing. We investigated the role of CD9 in the dissemination 
      of B acute lymphoblastic leukemia (B-ALL) cells, by stably downregulating CD9 in 
      REH and NALM6 cells. CD9 expression was associated with higher levels of REH cell 
      adhesion to fibronectin and C-X-C motif chemokine receptor 4 (CXCR4)-mediated 
      migration. Death occurred later in NOD/SCID mice receiving REH cells depleted of 
      CD9 for transplantation than in mice receiving control cells. After C-X-C motif 
      chemokine ligand 12 (CXCL12) stimulation, CD9 promoted the formation of long 
      cytoplasmic actin-rich protrusions. We demonstrated that CD9 enhanced RAC1 
      activation, in both REH cells and blasts from patients. Conversely, the 
      overexpression of a competing CD9 C-terminal tail peptide in REH cytoplasm 
      decreased RAC1 activation and cytoplasmic extension formation in response to 
      CXCL12. Finally, the inhibition of RAC1 activation decreased migration in vitro, 
      and the depletion of RAC1 protein from transplanted REH cells increased mouse 
      survival. Furthermore, a testis-conditioned medium induced the migration of REH 
      and NALM6 cells, and this migration was impeded by an anti-CD9 antibody. The 
      level of CD9 expression also influenced the homing of these cells in mouse 
      testes. These findings demonstrate, for the first time, that CD9 plays a key role 
      in the CXCR4-mediated migration and engraftment of B-ALL cells in the bone marrow 
      or testis, through RAC1 activation.
CI  - (c) 2015 by The American Society of Hematology.
FAU - Arnaud, Marie-Pierre
AU  - Arnaud MP
AD  - Centre National de la Recherche Scientifique (CNRS) Unites Mixtes de Recherche 
      (UMR) 6290, Institut de Genetique et Developpement de Rennes and Structure 
      Federative de Recherche (SFR) en Biologie et Sante de Rennes Biosit, Unite Mixte 
      de Service (UMS) CNRS 3480/US INSERM 018, Universite de Rennes 1, Rennes, France;
FAU - Vallee, Audrey
AU  - Vallee A
AD  - Centre National de la Recherche Scientifique (CNRS) Unites Mixtes de Recherche 
      (UMR) 6290, Institut de Genetique et Developpement de Rennes and Structure 
      Federative de Recherche (SFR) en Biologie et Sante de Rennes Biosit, Unite Mixte 
      de Service (UMS) CNRS 3480/US INSERM 018, Universite de Rennes 1, Rennes, France;
FAU - Robert, Guillaume
AU  - Robert G
AD  - Centre National de la Recherche Scientifique (CNRS) Unites Mixtes de Recherche 
      (UMR) 6290, Institut de Genetique et Developpement de Rennes and Structure 
      Federative de Recherche (SFR) en Biologie et Sante de Rennes Biosit, Unite Mixte 
      de Service (UMS) CNRS 3480/US INSERM 018, Universite de Rennes 1, Rennes, France; 
      Department of OncoPediatrics, Rennes University Hospital, Rennes, France;
FAU - Bonneau, Jacinthe
AU  - Bonneau J
AD  - Centre National de la Recherche Scientifique (CNRS) Unites Mixtes de Recherche 
      (UMR) 6290, Institut de Genetique et Developpement de Rennes and Structure 
      Federative de Recherche (SFR) en Biologie et Sante de Rennes Biosit, Unite Mixte 
      de Service (UMS) CNRS 3480/US INSERM 018, Universite de Rennes 1, Rennes, France; 
      Department of OncoPediatrics, Rennes University Hospital, Rennes, France;
FAU - Leroy, Christine
AU  - Leroy C
AD  - INSERM UMR U978, Adaptateurs de Signalisation en Hematologie, Universite Paris 
      13, Unite de Formation et de Recherche (UFR) de Sante, Medecine et Biologie 
      Humaine (SMBH), Bobigny, France; and.
FAU - Varin-Blank, Nadine
AU  - Varin-Blank N
AD  - INSERM UMR U978, Adaptateurs de Signalisation en Hematologie, Universite Paris 
      13, Unite de Formation et de Recherche (UFR) de Sante, Medecine et Biologie 
      Humaine (SMBH), Bobigny, France; and.
FAU - Rio, Anne-Gaelle
AU  - Rio AG
AD  - Centre National de la Recherche Scientifique (CNRS) Unites Mixtes de Recherche 
      (UMR) 6290, Institut de Genetique et Developpement de Rennes and Structure 
      Federative de Recherche (SFR) en Biologie et Sante de Rennes Biosit, Unite Mixte 
      de Service (UMS) CNRS 3480/US INSERM 018, Universite de Rennes 1, Rennes, France;
FAU - Troadec, Marie-Berengere
AU  - Troadec MB
AD  - Centre National de la Recherche Scientifique (CNRS) Unites Mixtes de Recherche 
      (UMR) 6290, Institut de Genetique et Developpement de Rennes and Structure 
      Federative de Recherche (SFR) en Biologie et Sante de Rennes Biosit, Unite Mixte 
      de Service (UMS) CNRS 3480/US INSERM 018, Universite de Rennes 1, Rennes, France;
FAU - Galibert, Marie-Dominique
AU  - Galibert MD
AD  - Centre National de la Recherche Scientifique (CNRS) Unites Mixtes de Recherche 
      (UMR) 6290, Institut de Genetique et Developpement de Rennes and Structure 
      Federative de Recherche (SFR) en Biologie et Sante de Rennes Biosit, Unite Mixte 
      de Service (UMS) CNRS 3480/US INSERM 018, Universite de Rennes 1, Rennes, France; 
      Department of Medical Genomic, Rennes University Hospital, Rennes, France.
FAU - Gandemer, Virginie
AU  - Gandemer V
AD  - Centre National de la Recherche Scientifique (CNRS) Unites Mixtes de Recherche 
      (UMR) 6290, Institut de Genetique et Developpement de Rennes and Structure 
      Federative de Recherche (SFR) en Biologie et Sante de Rennes Biosit, Unite Mixte 
      de Service (UMS) CNRS 3480/US INSERM 018, Universite de Rennes 1, Rennes, France; 
      Department of OncoPediatrics, Rennes University Hospital, Rennes, France;
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150828
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (CXCR4 protein, mouse)
RN  - 0 (Cd9 protein, mouse)
RN  - 0 (Chemokine CXCL12)
RN  - 0 (Cxcl12 protein, mouse)
RN  - 0 (Neuropeptides)
RN  - 0 (RNA, Messenger)
RN  - 0 (Rac1 protein, mouse)
RN  - 0 (Receptors, CXCR4)
RN  - 0 (Tetraspanin 29)
RN  - EC 3.6.5.2 (rac1 GTP-Binding Protein)
SB  - IM
MH  - Animals
MH  - Apoptosis
MH  - Blotting, Western
MH  - Bone Marrow/metabolism/pathology
MH  - Cell Adhesion
MH  - *Cell Movement
MH  - Cell Proliferation
MH  - Chemokine CXCL12/metabolism
MH  - *Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Immunoprecipitation
MH  - Male
MH  - Mice
MH  - Mice, Inbred NOD
MH  - Mice, SCID
MH  - Neuropeptides/*metabolism
MH  - Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/*metabolism/*pathology
MH  - RNA, Messenger/genetics
MH  - Real-Time Polymerase Chain Reaction
MH  - Receptors, CXCR4/*metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Signal Transduction
MH  - Testis/metabolism/pathology
MH  - Tetraspanin 29/*metabolism
MH  - Tumor Cells, Cultured
MH  - Xenograft Model Antitumor Assays
MH  - rac1 GTP-Binding Protein/*metabolism
EDAT- 2015/09/01 06:00
MHDA- 2016/01/20 06:00
CRDT- 2015/08/31 06:00
PHST- 2015/02/17 00:00 [received]
PHST- 2015/07/22 00:00 [accepted]
PHST- 2015/08/31 06:00 [entrez]
PHST- 2015/09/01 06:00 [pubmed]
PHST- 2016/01/20 06:00 [medline]
AID - S0006-4971(20)30845-4 [pii]
AID - 10.1182/blood-2015-02-628560 [doi]
PST - ppublish
SO  - Blood. 2015 Oct 8;126(15):1802-12. doi: 10.1182/blood-2015-02-628560. Epub 2015 
      Aug 28.