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Cited by 20Acute Myeloid Leukemia ResearchMitochondrial Function and PathologyChronic Myeloid Leukemia Treatments

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Mitochondrial Dysfunction in Human Leukemic Stem/Progenitor Cells upon Loss of RAC2

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Capala, Marta E., Maat, Henny, Bonardi, Francesco, van den Boom, Vincent, Kuipers, Jeroen, Vellenga, Edo, Giepmans, Ben N. G., Schuringa, Jan Jacob·2015·PLOS ONE
DOI 10.1371/journal.pone.0128585PMC PMC4446344
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Abstract

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.

Overview

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TL;DR

In BCR-ABL-transduced human hematopoietic stem/progenitor cells, RAC2 depletion—but not RAC1 depletion—impairs proliferation/self-renewal and causes mitochondrial dysfunction, including decreased membrane potential and abnormal cristae. RAC2 specifically interacts with mitochondrial transport proteins SAM50 and Metaxin 1, and SAM50 knockdown phenocopies key defects, suggesting RAC2 maintains mitochondrial integrity in leukemic stem/progenitor cells.

Key findings

  • RAC2 depletion in BCR-ABL CD34+ cord blood cells reduced proliferation, progenitor frequency, cobblestone formation, and replating capacity; LTC-IC frequency was 1:57 vs. 1:11 for control (p = 0.0001), while RAC1 depletion had little effect.
  • RAC2-depleted BCR-ABL cells showed decreased mitochondrial membrane potential by DilC FACS, unchanged mitochondrial mass by MitoTracker Red, and reduced ROS that did not reach statistical significance; EM showed concentric cristae in almost one-third of RAC2-depleted cells vs. few control cells (131 control and 139 shRAC2 cells analyzed).
  • Proteomics identified 335 RAC1-specific and 229 RAC2-specific peptides; RAC2 interacted with mitochondrial outer membrane/transport proteins including SAM50 and Metaxin 1, confirmed by co-immunoprecipitation, and SAM50 knockdown impaired proliferation/replating and reduced mitochondrial membrane potential.
  • Primary BC CML CD34+ cells also showed a proliferative disadvantage upon RAC2 downregulation, with little effect from RAC1 depletion.

Methods

  • shRNA knockdown of RAC1, RAC2, or SAM50 in BCR-ABL-transduced CD34+ cord blood HSPCs and primary BC CML CD34+ cells; MS5 stromal long-term co-cultures, CFC, LTC-IC limiting dilution, and replating assays.
  • Flow cytometry for mitochondrial membrane potential (DilC1), mitochondrial mass (MitoTracker Red), ROS (CellROX), apoptosis (Annexin V), and cell cycle; automated electron microscopy/Nanotomy; qRT-PCR; Western blot.
  • Proteomics used Avi-tagged RAC1/RAC2 with BirA in K562 cells, streptavidin pull-down, LC-MS/MS, GFP pull-down, and anti-SAM50 co-IP; DAVID GO annotation; Student’s t test with p < 0.05.

Limitations

  • Stated: studies on a wider collection of leukemic samples are necessary; further studies are required to resolve whether SAM50 knockdown affects RAC2 stability; more experiments are needed to determine the exact molecular mechanisms.
  • Evident: primary BC CML validation used a single patient (Methods says patient 2007–048; Fig 1 legend says 2007–043), and much mechanistic work used K562/TF-1 cell lines and in vitro stromal co-cultures rather than in vivo models.
  • Evident: ROS reduction upon RAC2 downregulation did not reach statistical significance, and some co-IP controls showed background, although SAM50 and Metaxin 1 were enriched in RAC2 fractions.

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Crossref · 10.1371/journal.pone.0128585

Cites

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Figures

Fig 1 Human BCR-ABL-transduced HSPCs specifically depend on RAC2, but not RAC1 expression. (A) Cord blood (CB) CD34+ stem/progenitor cells were co-transduced with a retroviral construct for BCR-ABL and either a control scrambled shRNA vector (shSCR) or with RAC1/RAC2-targeting shRNA vectors (shRAC1 or shRAC2). Transduced cells were sorted, cultured on stroma for 10 days and used for RNA extraction. Quantitative PCR was performed to measure RAC1 (left panel) or RAC2 mRNA levels (right panel) normalized against RPL27 mRNA. (B) CB CD34+ stem/progenitor cells were co-transduced with BCR-ABL and either control shSCR or with shRAC1 or shRAC2. 5x103 double-transduced cells were sorted per group and plated on MS5 stromal cells. Cultures were demi-depopulated on indicated days for analysis and replated as indicated. The cumulative cell growth is shown for a representative experiment out of 7 independent experiments. (C) Fold reduction of cumulative cell growth of BCR-ABL and shRAC2-double-transduced CD34+ CB cells in long-term co-culture as described in panel B, normalized to control cells. Cumulative expansion curves of 7 independent experiments are shown. (D) Suspension cells from MS5 co-cultures as described in panel B were analyzed for progenitor frequency by CFC assay at week 1 and week 2 of the co-culture. 104 cells from each co-culture were plated in a CFC assay in methylcellulose in duplicate, and colonies were evaluated 2 weeks after plating. Total CFC numbers are shown from a representative of 5 independent experiments. Error bars indicate standard deviation. (E) LTC-IC frequencies were determined in limiting dilution on MS5 stromal cells. After 5 weeks of culture methylcellulose was added and colonies were scored two weeks later. Poisson statistics were used to calculate LTC-IC frequencies (p = 0.1 for shSCR vs shRAC1 and p = 0.0001 for shSCR vs shRAC2). (F) BC CML CD34+ cells (patient 2007–043) were sorted and plated on MS5 stroma. Cells were allowed to proliferate for 5 days after which RAC inhibitor was added to the following concentrations: 10μM, 20μM or 40μM. Co-cultures were demi-depopulated on indicated days for analysis. Cumulative cell count is shown as an average of 3 independent experiments. Error bars represent standard deviation. (G) BC CML CD34+ cells (patient 2007–043) were transduced with either control shSCR or with shRAC1 or shRAC2. 5x104 transduced cells were sorted per group and plated on MS5 stromal cells; cultures were demi-depopulated weekly for analysis. Cumulative cell growth is shown as an average of 3 independent experiments. Error bars represent standard deviation. * P<0.05, ** P<0.01.
Fig 1 Human BCR-ABL-transduced HSPCs specifically depend on RAC2, but not RAC1 expression. (A) Cord blood (CB) CD34+ stem/progenitor cells were co-transduced with a retroviral construct for BCR-ABL and either a control scrambled shRNA vector (shSCR) or with RAC1/RAC2-targeting shRNA vectors (shRAC1 or shRAC2). Transduced cells were sorted, cultured on stroma for 10 days and used for RNA extraction. Quantitative PCR was performed to measure RAC1 (left panel) or RAC2 mRNA levels (right panel) normalized against RPL27 mRNA. (B) CB CD34+ stem/progenitor cells were co-transduced with BCR-ABL and either control shSCR or with shRAC1 or shRAC2. 5x103 double-transduced cells were sorted per group and plated on MS5 stromal cells. Cultures were demi-depopulated on indicated days for analysis and replated as indicated. The cumulative cell growth is shown for a representative experiment out of 7 independent experiments. (C) Fold reduction of cumulative cell growth of BCR-ABL and shRAC2-double-transduced CD34+ CB cells in long-term co-culture as described in panel B, normalized to control cells. Cumulative expansion curves of 7 independent experiments are shown. (D) Suspension cells from MS5 co-cultures as described in panel B were analyzed for progenitor frequency by CFC assay at week 1 and week 2 of the co-culture. 104 cells from each co-culture were plated in a CFC assay in methylcellulose in duplicate, and colonies were evaluated 2 weeks after plating. Total CFC numbers are shown from a representative of 5 independent experiments. Error bars indicate standard deviation. (E) LTC-IC frequencies were determined in limiting dilution on MS5 stromal cells. After 5 weeks of culture methylcellulose was added and colonies were scored two weeks later. Poisson statistics were used to calculate LTC-IC frequencies (p = 0.1 for shSCR vs shRAC1 and p = 0.0001 for shSCR vs shRAC2). (F) BC CML CD34+ cells (patient 2007–043) were sorted and plated on MS5 stroma. Cells were allowed to proliferate for 5 days after which RAC inhibitor was added to the following concentrations: 10μM, 20μM or 40μM. Co-cultures were demi-depopulated on indicated days for analysis. Cumulative cell count is shown as an average of 3 independent experiments. Error bars represent standard deviation. (G) BC CML CD34+ cells (patient 2007–043) were transduced with either control shSCR or with shRAC1 or shRAC2. 5x104 transduced cells were sorted per group and plated on MS5 stromal cells; cultures were demi-depopulated weekly for analysis. Cumulative cell growth is shown as an average of 3 independent experiments. Error bars represent standard deviation. * P<0.05, ** P<0.01.CC BY · PubMed Central
Fig 2 Depletion of RAC2 impairs expansion of primitive leukemic cobblestone cells. CB CD34+ stem/progenitor cells were double-transduced with BCR-ABL and either control scrambled shRNA vector (shSCR) or with RAC2-targeting shRNA vector (shRAC2) and 2X103 double-transduced cells were plated on MS5 stromal cells, co-cultures were evaluated daily and images of cobblestones we acquired for 14 days (four representative images of each are shown in A). (B) The total number of cobblestones present in the culture of control or shRAC2-transduced BCR-ABL cells is shown for the indicated time points. (C) Acquired images of cobblestones were overlaid with a grid and the number of cells per individual cobblestone was counted for control and shRAC2-transduced cells, for the time points as in panel B. (D) CB CD34+ stem/progenitor cells were double-transduced with BCR-ABL and either control scrambled shRNA vector (shSCR) or with RAC2-targeting shRNA vectors (shRAC2) and 5x103 double-transduced cells were sorted and plated on MS5 stromal cells. After 10 days of co-culture cobblestone cells were harvested and Annexin V staining was performed to measure apoptosis. The average of three independent experiments is shown. Error bars represent standard deviation. (E) Cobblestone cells from cultures like described in panel D were harvested and used for staining in hypotonic PI solution to evaluate cell cycle distribution. The average of three independent experiments is shown. Error bars represent standard deviation. * P<0.05, ** P<0.01.
Fig 2 Depletion of RAC2 impairs expansion of primitive leukemic cobblestone cells. CB CD34+ stem/progenitor cells were double-transduced with BCR-ABL and either control scrambled shRNA vector (shSCR) or with RAC2-targeting shRNA vector (shRAC2) and 2X103 double-transduced cells were plated on MS5 stromal cells, co-cultures were evaluated daily and images of cobblestones we acquired for 14 days (four representative images of each are shown in A). (B) The total number of cobblestones present in the culture of control or shRAC2-transduced BCR-ABL cells is shown for the indicated time points. (C) Acquired images of cobblestones were overlaid with a grid and the number of cells per individual cobblestone was counted for control and shRAC2-transduced cells, for the time points as in panel B. (D) CB CD34+ stem/progenitor cells were double-transduced with BCR-ABL and either control scrambled shRNA vector (shSCR) or with RAC2-targeting shRNA vectors (shRAC2) and 5x103 double-transduced cells were sorted and plated on MS5 stromal cells. After 10 days of co-culture cobblestone cells were harvested and Annexin V staining was performed to measure apoptosis. The average of three independent experiments is shown. Error bars represent standard deviation. (E) Cobblestone cells from cultures like described in panel D were harvested and used for staining in hypotonic PI solution to evaluate cell cycle distribution. The average of three independent experiments is shown. Error bars represent standard deviation. * P<0.05, ** P<0.01.CC BY · PubMed Central
Fig 3 Depletion of RAC2 causes mitochondrial dysfunction in BCR-ABL-expressing HSPCs. (A) 5x103 BCR-ABL and shSCR or shRAC2 double-transduced cells were sorted and plated on MS5 stromal cells. Suspension cells were harvested after 14 days of co-culture and stained with DilC to measure changes in mitochondrial membrane potential. Representative FACS plots are shown. Quantification of FACS measurements represented as changes in MFI relative to control is shown below. The average of four independent experiments is shown with standard deviation. (B) Suspension cells from the double-transduced co-cultures like described in panel A were harvested after 12 days and stained with MitotrackerRed to measure mitochondrial mass. A representative FACS plot is shown. Quantification of FACS measurements represented as MFI relative to control is shown below. Average of three independent experiments is shown with standard deviation. (C) Suspension cells from the double-transduced co-cultures (BCR-ABL and shSCR or shRAC2) were harvested after 12 days and stained with CellROX to measure oxidative stress. A representative FACS plot is shown. Quantification of FACS measurements represented as MFI relative to control is shown below. Average of three independent experiments is shown with standard deviation. (D) BCR-ABL and shRNA double-transduced cells expanded in stromal co-cultures for 7 days were harvested, pelleted and embedded in EPON, and ultrathin sections were analyzed by STEM. Large area scans of high resolution were acquired allowing evaluation of the ultrastructure of mitochondria in large number of control cells (D) or shRAC2-transduced cells (E), representative images of the abnormalities in the structure of mitochondria are shown). (F) 131 control and 139 shRAC2-transduced cells were analyzed for the presence of mitochondrial abnormalities (as seen in E) and the cells with aberrant mitochondria were enumerated. ** P<0.01.
Fig 3 Depletion of RAC2 causes mitochondrial dysfunction in BCR-ABL-expressing HSPCs. (A) 5x103 BCR-ABL and shSCR or shRAC2 double-transduced cells were sorted and plated on MS5 stromal cells. Suspension cells were harvested after 14 days of co-culture and stained with DilC to measure changes in mitochondrial membrane potential. Representative FACS plots are shown. Quantification of FACS measurements represented as changes in MFI relative to control is shown below. The average of four independent experiments is shown with standard deviation. (B) Suspension cells from the double-transduced co-cultures like described in panel A were harvested after 12 days and stained with MitotrackerRed to measure mitochondrial mass. A representative FACS plot is shown. Quantification of FACS measurements represented as MFI relative to control is shown below. Average of three independent experiments is shown with standard deviation. (C) Suspension cells from the double-transduced co-cultures (BCR-ABL and shSCR or shRAC2) were harvested after 12 days and stained with CellROX to measure oxidative stress. A representative FACS plot is shown. Quantification of FACS measurements represented as MFI relative to control is shown below. Average of three independent experiments is shown with standard deviation. (D) BCR-ABL and shRNA double-transduced cells expanded in stromal co-cultures for 7 days were harvested, pelleted and embedded in EPON, and ultrathin sections were analyzed by STEM. Large area scans of high resolution were acquired allowing evaluation of the ultrastructure of mitochondria in large number of control cells (D) or shRAC2-transduced cells (E), representative images of the abnormalities in the structure of mitochondria are shown). (F) 131 control and 139 shRAC2-transduced cells were analyzed for the presence of mitochondrial abnormalities (as seen in E) and the cells with aberrant mitochondria were enumerated. ** P<0.01.CC BY · PubMed Central
Fig 4 RAC1 and RAC2 interact with distinct sets of proteins. K562 cells were transduced with retroviral constructs containing Avi-tagged RAC1 (Avi-RAC1) or RAC2 (Avi-RAC2) and BirA biotin ligase, or BirA-only control construct (BirA) sorted, and streptavidin-based pull-down assay was performed. Bound fractions were then used for mass spectrometry analysis to identify RAC1- or RAC2-specific interaction partners (experimental setup shown in A). (B) Efficiency of the pull-down assay was assessed by Western blot detecting Avi-tagged RAC1 and RAC2. T: total cell lysate fraction; B: bound fraction; NB: non-bound fraction. (C) Mass spectrometry analysis identified 335 RAC1-specific and 229-RAC2-specific peptides using 90% protein/90% peptide confidence cut-off. (D) Cytospins of GFP-RAC1- or GFP-RAC2-transduced TF-1 cells were analyzed for RAC localization. Syto62 was used to stain the nucleus.
Fig 4 RAC1 and RAC2 interact with distinct sets of proteins. K562 cells were transduced with retroviral constructs containing Avi-tagged RAC1 (Avi-RAC1) or RAC2 (Avi-RAC2) and BirA biotin ligase, or BirA-only control construct (BirA) sorted, and streptavidin-based pull-down assay was performed. Bound fractions were then used for mass spectrometry analysis to identify RAC1- or RAC2-specific interaction partners (experimental setup shown in A). (B) Efficiency of the pull-down assay was assessed by Western blot detecting Avi-tagged RAC1 and RAC2. T: total cell lysate fraction; B: bound fraction; NB: non-bound fraction. (C) Mass spectrometry analysis identified 335 RAC1-specific and 229-RAC2-specific peptides using 90% protein/90% peptide confidence cut-off. (D) Cytospins of GFP-RAC1- or GFP-RAC2-transduced TF-1 cells were analyzed for RAC localization. Syto62 was used to stain the nucleus.CC BY · PubMed Central
Fig 5 RAC2 interaction with mitochondrial transport proteins is required for the long-term expansion of human BCR-ABL-expressing HSPCs. (A) Schematic representation of the mitochondrial transport complexes and their function. (B) K562 cells transduced with retroviral constructs containing Avi-tagged RAC2 (Avi-RAC2) and BirA biotin ligase, or BirA-only control construct (BirA) were sorted, and streptavidin-based pull-down assay was performed. Conversely, immunoprecipitation with anti-SAM50 antibody was performed. Alternatively, K562 cells were transduced with lentiviral GFP-tagged RAC2 (GFP-RAC2) and pull-down assay using GFP-affinity beads was performed. Empty GFP vector-transduced cells were used as a control. Efficiency of pull-down assay was assessed by Western blot detecting either SAM50 or Metaxin 1 (Streptavidin and GFP pull-down), or GFP (SAM50 pull-down). T: total cell lysate fraction; B: bound fraction; NB: non-bound fraction. (C) K562 cells transduced with the control scrambled shRNA vector (shSCR) or with the SAM50-targeting shRNA vector (shSAM50) were sorted and used for Western blot analysis to determine SAM50 protein levels. The quantification of protein expression normalized to control is indicated above each lane. (D) CB CD34+ stem/progenitor cells were double-transduced with BCR-ABL and either control shSCR or with shSAM50. 5*103 double-transduced cells were sorted per group and plated on MS5 stromal cells. Cultures were demi-depopulated on indicated days for analysis and replated where indicated. Cumulative cell growth is shown for two representative experiments of 4 independent experiments. (E) 5*103 BCR-ABL and shSCR or shSAM50 double-transduced cells were sorted and plated on MS5 stromal cells. Suspension cells were harvested after 14 days of co-culture and stained with DilC to measure changes in mitochondrial membrane potential. Representative FACS plots are shown. (F) Quantification of FACS measurements as described in panel (E) represented as changes in MFI relative to control is shown below. Average of four independent experiments is shown with standard deviation. * P<0.05.
Fig 5 RAC2 interaction with mitochondrial transport proteins is required for the long-term expansion of human BCR-ABL-expressing HSPCs. (A) Schematic representation of the mitochondrial transport complexes and their function. (B) K562 cells transduced with retroviral constructs containing Avi-tagged RAC2 (Avi-RAC2) and BirA biotin ligase, or BirA-only control construct (BirA) were sorted, and streptavidin-based pull-down assay was performed. Conversely, immunoprecipitation with anti-SAM50 antibody was performed. Alternatively, K562 cells were transduced with lentiviral GFP-tagged RAC2 (GFP-RAC2) and pull-down assay using GFP-affinity beads was performed. Empty GFP vector-transduced cells were used as a control. Efficiency of pull-down assay was assessed by Western blot detecting either SAM50 or Metaxin 1 (Streptavidin and GFP pull-down), or GFP (SAM50 pull-down). T: total cell lysate fraction; B: bound fraction; NB: non-bound fraction. (C) K562 cells transduced with the control scrambled shRNA vector (shSCR) or with the SAM50-targeting shRNA vector (shSAM50) were sorted and used for Western blot analysis to determine SAM50 protein levels. The quantification of protein expression normalized to control is indicated above each lane. (D) CB CD34+ stem/progenitor cells were double-transduced with BCR-ABL and either control shSCR or with shSAM50. 5*103 double-transduced cells were sorted per group and plated on MS5 stromal cells. Cultures were demi-depopulated on indicated days for analysis and replated where indicated. Cumulative cell growth is shown for two representative experiments of 4 independent experiments. (E) 5*103 BCR-ABL and shSCR or shSAM50 double-transduced cells were sorted and plated on MS5 stromal cells. Suspension cells were harvested after 14 days of co-culture and stained with DilC to measure changes in mitochondrial membrane potential. Representative FACS plots are shown. (F) Quantification of FACS measurements as described in panel (E) represented as changes in MFI relative to control is shown below. Average of four independent experiments is shown with standard deviation. * P<0.05.CC BY · PubMed Central

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Metadata

Authors
Capala, M. E., Maat, H., Bonardi, F., van den Boom, V., Kuipers, J., Vellenga, E., Giepmans, B. N. G., & Schuringa, J. J.
Affiliations
University Medical Center Groningen (NL)
Corresponding author
Schuringa, Jan Jacob
ORCID
Venue
PLOS ONE
Publisher
Public Library of Science (PLoS)
Published
2015-05-27
Volume
10
Issue
5
Pages
e0128585
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0128585
PMC
PMC4446344
OpenAlex
W2102434735
Cited by
20
References
50
Citations by year
2026: 3 · 2023: 2 · 2021: 2 · 2020: 2 · 2019: 3 · 2018: 4 · 2017: 2 · 2016: 2
FWCI
1.77
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
Funders
  • ZonMw (91111.006, 91111)
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (91111, ZonMW 91111.006, 91111.006)
Topics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
Keywords
Rac2, Rac1, leukemia stem cells, hematopoietic stem and progenitor cells, BCR-ABL, mitochondrial dysfunction, mitochondrial membrane potential, mitochondrial ultrastructure, Sam50, mitochondrial transport proteins, self-renewal, apoptosis, cell cycle, Rac GTPase
MeSH terms
Mitochondrial Precursor Protein Import Complex Proteins, RAC2 GTP-Binding Protein, Bone Marrow Cells, Cell Cycle, Cell Line, Hematopoietic Stem Cells, Humans, Membrane Proteins, Mitochondria, Proteins, Stem Cells, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Down-Regulation, Fusion Proteins, bcr-abl, Apoptosis, rac GTP-Binding Proteins, Mitochondrial Proteins, Mitochondrial Diseases, Mitochondrial Membrane Transport Proteins, Immunoprecipitation, Cell Proliferation, Membrane Potential, Mitochondrial, HEK293 Cells

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CoChat. (2026). Citation check: Mitochondrial Dysfunction in Human Leukemic Stem/Progenitor Cells upon Loss of RAC2. https://app.cochat.ai/papers/10.1371/journal.pone.0128585
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Capala, M. E., Maat, H., Bonardi, F., van den Boom, V., Kuipers, J., Vellenga, E., Giepmans, B. N. G., & Schuringa, J. J. (2015). Mitochondrial Dysfunction in Human Leukemic Stem/Progenitor Cells upon Loss of RAC2. PLOS ONE. https://doi.org/10.1371/journal.pone.0128585