PMID- 26016997
OWN - NLM
STAT- MEDLINE
DCOM- 20160405
LR  - 20231213
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 10
IP  - 5
DP  - 2015
TI  - Mitochondrial Dysfunction in Human Leukemic Stem/Progenitor Cells upon Loss of 
      RAC2.
PG  - e0128585
LID - 10.1371/journal.pone.0128585 [doi]
LID - e0128585
AB  - Leukemic stem cells (LSCs) reside within bone marrow niches that maintain their 
      relatively quiescent state and convey resistance to conventional treatment. Many 
      of the microenvironmental signals converge on RAC GTPases. Although it has become 
      clear that RAC proteins fulfill important roles in the hematopoietic compartment, 
      little has been revealed about the downstream effectors and molecular mechanisms. 
      We observed that in BCR-ABL-transduced human hematopoietic stem/progenitor cells 
      (HSPCs) depletion of RAC2 but not RAC1 induced a marked and immediate decrease in 
      proliferation, progenitor frequency, cobblestone formation and replating 
      capacity, indicative for reduced self-renewal. Cell cycle analyses showed reduced 
      cell cycle activity in RAC2-depleted BCR-ABL leukemic cobblestones coinciding 
      with an increased apoptosis. Moreover, a decrease in mitochondrial membrane 
      potential was observed upon RAC2 downregulation, paralleled by severe 
      mitochondrial ultrastructural malformations as determined by automated electron 
      microscopy. Proteome analysis revealed that RAC2 specifically interacted with a 
      set of mitochondrial proteins including mitochondrial transport proteins SAM50 
      and Metaxin 1, and interactions were confirmed in independent 
      co-immunoprecipitation studies. Downregulation of SAM50 also impaired the 
      proliferation and replating capacity of BCR-ABL-expressing cells, again 
      associated with a decreased mitochondrial membrane potential. Taken together, 
      these data suggest an important role for RAC2 in maintaining mitochondrial 
      integrity.
FAU - Capala, Marta E
AU  - Capala ME
AD  - Department of Experimental Hematology, Cancer Research Center Groningen, 
      Groningen, the Netherlands.
FAU - Maat, Henny
AU  - Maat H
AD  - Department of Experimental Hematology, Cancer Research Center Groningen, 
      Groningen, the Netherlands.
FAU - Bonardi, Francesco
AU  - Bonardi F
AD  - Department of Experimental Hematology, Cancer Research Center Groningen, 
      Groningen, the Netherlands.
FAU - van den Boom, Vincent
AU  - van den Boom V
AD  - Department of Experimental Hematology, Cancer Research Center Groningen, 
      Groningen, the Netherlands.
FAU - Kuipers, Jeroen
AU  - Kuipers J
AD  - Department of Cell Biology, University Medical Center Groningen, University of 
      Groningen, Groningen, the Netherlands.
FAU - Vellenga, Edo
AU  - Vellenga E
AD  - Department of Experimental Hematology, Cancer Research Center Groningen, 
      Groningen, the Netherlands.
FAU - Giepmans, Ben N G
AU  - Giepmans BN
AD  - Department of Experimental Hematology, Cancer Research Center Groningen, 
      Groningen, the Netherlands.
FAU - Schuringa, Jan Jacob
AU  - Schuringa JJ
AD  - Department of Experimental Hematology, Cancer Research Center Groningen, 
      Groningen, the Netherlands.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150527
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (MTX1 protein, human)
RN  - 0 (Membrane Proteins)
RN  - 0 (Mitochondrial Membrane Transport Proteins)
RN  - 0 (Mitochondrial Precursor Protein Import Complex Proteins)
RN  - 0 (Mitochondrial Proteins)
RN  - 0 (Proteins)
RN  - 0 (SAMM50 protein, human)
RN  - EC 2.7.10.2 (Fusion Proteins, bcr-abl)
RN  - EC 3.6.5.2 (rac GTP-Binding Proteins)
SB  - IM
MH  - Apoptosis/genetics
MH  - Bone Marrow Cells/metabolism/pathology
MH  - Cell Cycle/genetics
MH  - Cell Line
MH  - Cell Proliferation/genetics
MH  - Down-Regulation/genetics
MH  - Fusion Proteins, bcr-abl/genetics
MH  - HEK293 Cells
MH  - Hematopoietic Stem Cells/*metabolism/pathology
MH  - Humans
MH  - Immunoprecipitation/methods
MH  - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics/pathology
MH  - Membrane Potential, Mitochondrial/genetics
MH  - Membrane Proteins/genetics
MH  - Mitochondria/*genetics/pathology
MH  - Mitochondrial Diseases/*genetics/pathology
MH  - Mitochondrial Membrane Transport Proteins
MH  - Mitochondrial Precursor Protein Import Complex Proteins
MH  - Mitochondrial Proteins/genetics
MH  - Proteins/genetics
MH  - Stem Cells/*metabolism/pathology
MH  - rac GTP-Binding Proteins/*genetics
MH  - RAC2 GTP-Binding Protein
PMC - PMC4446344
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2015/05/29 06:00
MHDA- 2016/04/06 06:00
PMCR- 2015/05/27
CRDT- 2015/05/29 06:00
PHST- 2015/01/29 00:00 [received]
PHST- 2015/04/28 00:00 [accepted]
PHST- 2015/05/29 06:00 [entrez]
PHST- 2015/05/29 06:00 [pubmed]
PHST- 2016/04/06 06:00 [medline]
PHST- 2015/05/27 00:00 [pmc-release]
AID - PONE-D-15-03737 [pii]
AID - 10.1371/journal.pone.0128585 [doi]
PST - epublish
SO  - PLoS One. 2015 May 27;10(5):e0128585. doi: 10.1371/journal.pone.0128585. 
      eCollection 2015.