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Rac2 GTPase deficiency depletes BCR-ABL+ leukemic stem cells and progenitors in vivo
Open accessAbstract
Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disease (MPD) initiated by p210-BCR-ABL–mediated transformation of hematopoietic stem cells (HSCs). Inhibition of the ABL kinase alone is not sufficient to eradicate leukemic stem cells (LSCs). We have previously shown that the deficiency of Rac2 GTPase signaling, but not Rac1, in p210-BCR-ABL–transduced hematopoietic cells prolonged survival of mice with MPD. Here we demonstrate that absence of Rac2 GTPase prolongs survival of HSC-initiated, inducible Scl/p210-BCR-ABL (Scl/p210) binary transgenic mice, it induces apoptosis, and, unlike in normal HSC and progenitor (HSC/P), impairs LSC and progenitor (LSC/P) proliferation in vivo. As a result, Rac2 deficiency causes functional exhaustion of the LSC pool in vivo. This defect is not due to impaired interaction with the hematopoietic microenvironment as reflected by its unaltered adhesion, migration, and homing to recipient organs. In summary, Rac2 deficiency exhausts the LSC pool in vivo through impairment of oncogene-induced proliferation and survival signals.
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TL;DR
Rac2 GTPase deficiency prolongs survival in an HSC-initiated inducible Scl/p210-BCR-ABL mouse model of CML by reducing leukemic stem/progenitor proliferation and increasing apoptosis, leading to functional exhaustion of the leukemic stem cell pool. The defect is not explained by altered homing, adhesion, or migration.
Key findings
- Rac2 deficiency significantly prolonged survival of Scl/p210 mice; Scl/p210 mice showed 50% mortality after 8 months, and Rac2 deficiency alone significantly prolonged survival in vivo.
- Scl/p210;Rac2−/− mice had lower tumor-initiating LK and LSK cell content despite similar BCR-ABL expression (average ΔCt Scl/p210 = 7.00 vs Scl/p210;Rac2−/− = 6.01; 4 mice per group). Circulating LSK cells were 2-fold reduced (0.014% ± 0.007% vs 0.036% ± 0.02%; P < .05, n = 10 mice per group).
- Absence of Rac2 significantly reduced proliferation of Scl/p210 cells to levels similar to nonleukemic HSC/P, but did not modify proliferation of normal LK and LSK cells in vivo; Rac2 deficiency also induced apoptosis.
- Scl/p210;Rac2−/− cells showed significantly reduced long-term HSC engraftment and could not compete with normal HSCs in primary-to-secondary competitive repopulation, while homing to BM and spleen, adhesion, and migration were not altered.
Methods
- FVB/N-backcrossed Scl/p210-BCR-ABL mice were crossed with C57Bl/6 Rac2−/− mice to generate F2 Scl/p210;Rac2−/− mice; Rac-expressing Scl/p210 littermates were controls. Mice weaned from doxycycline for 3 months were used for assays.
- Assays included qPCR for genomic b3a2 and murine ApoB, in vivo BrdU incorporation for proliferation, activated caspase 3 flow cytometry for survival, adhesion and migration assays, homing assays, and competitive repopulation using CD45.1+ B6.SJLPtprca Pep3b/BoyJ recipients and competitor cells.
- Engraftment after transplantation was measured by chimera assessment by flow cytometry and qPCR of peripheral blood.
Limitations
- The paper does not state limitations in a dedicated section.
- Evident from the text: findings are from a mouse transgenic model (Scl/p210;Rac2−/−) rather than human CML samples, and several supporting analyses are reported in supplemental figures.
- Evident from the text: the study tests Rac2 deficiency rather than a pharmacologic Rac2 inhibitor, so direct therapeutic targeting is not established here.
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18 Own result · 9 Own interpretation · 8 Check pending · 5 No full text of the sources · 3 Not checked yet
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the absence of Rac2 significantly reduced proliferation of Scl/p210 to levels similar to nonleukemic HSC/P”
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This defect is not due to impaired interaction with the hematopoietic microenvironment as reflected by its unaltered adhesion, migration, and homing to recipient organs.”
- Also stated in: § Results and discussion · plain
“Scl/p210 and Scl/p210;Rac2−/− hematopoietic progenitors home to BM and spleen similarly”
- Also stated in: § Results and discussion · plain
“deletion of Rac2 did not affect the adhesion and migration-related transformation phenotype of Scl/p210 progenitors”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Results and discussion · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“unlike in normal HSC and progenitor (HSC/P), impairs LSC and progenitor (LSC/P) proliferation in vivo.”
- Also stated in: § Results and discussion · plain
“the absence of Rac2 significantly reduced proliferation of Scl/p210 to levels similar to nonleukemic HSC/P, but did not modify the proliferation of normal LK and LSK cells in vivo”
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Results and discussion · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Prolonged survival of Scl/p210;Rac2−/− mice was associated with lower content of tumor-initiating LK and LSK cells in vivo (Figure 1B-C)”
plainstates an associationn = 4- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Scl/p210;Rac2−/− cells showed significantly reduced long-term HSC engraftment”
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“RAC activity has been implicated in the disease initiation and maintenance in various murine leukemia models, including BCR-ABL and MLL-AF9-driven transformation [29–32].”
From Mitochondrial Dysfunction in Human Leukemic Stem/Progenitor Cells upon Loss of RAC2 (2015) · cites this paper as [30]
In the citing paper
“RAC GTPases are necessary for development and maintenance of leukemia in various murine models, including BCR-ABL-mediated transformation [30–32].”
From Mitochondrial Dysfunction in Human Leukemic Stem/Progenitor Cells upon Loss of RAC2 (2015) · cites this paper as [30]
In the citing paper
“In particular, RAC2 was shown to be critical for the development of BCR-ABL-mediated malignancy [30,44].”
From Mitochondrial Dysfunction in Human Leukemic Stem/Progenitor Cells upon Loss of RAC2 (2015) · cites this paper as [30]
Citations
Cites
Daley, G. Q., Van Etten, R. A., & Baltimore, D. (1990) · Science · doi:10.1126/science.2406902 · Cited by 1,756
Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML
Jamieson, C. H. M., Ailles, L. E., Dylla, S. J., Muijtjens, M., Jones, C., Zehnder, J. L., Gotlib, J., Li, K., Manz, M. G., Keating, A., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa040258 · Cited by 1,485
Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells
Yilmaz, Ö. H., Valdez, R., Theisen, B. K., Guo, W., Ferguson, D. O., Wu, H., & Morrison, S. J. (2006) · Nature · doi:10.1038/nature04703 · Cited by 1,113
Absence of blood formation in mice lacking the T-cell leukaemia oncoprotein tal-1/SCL
Shivdasani, R. A., Mayer, E. L., & Orkin, S. H. (1995) · Nature · doi:10.1038/373432a0 · Cited by 938
Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia
Ren, R. (2005) · Nature Reviews Cancer · doi:10.1038/nrc1567 · Cited by 878
Roberts, A. W., Kim, C., Zhen, L., Lowe, J. B., Kapur, R., Petryniak, B., Spaetti, A., Pollock, J. D., Borneo, J. B., Bradford, G. B., et al. (1999) · Immunity · doi:10.1016/s1074-7613(00)80019-9 · Cited by 556
Self-citationHematopoietic Cell Regulation by Rac1 and Rac2 Guanosine Triphosphatases
Gu, Y., Filippi, M.-D., Cancelas, J. A., Siefring, J. E., Williams, E. P., Jasti, A. C., Harris, C. E., Lee, A. W., Prabhakar, R., Atkinson, S. J., et al. (2003) · Science · doi:10.1126/science.1088485 · Cited by 510
Self-citationBethesda proposals for classification of nonlymphoid hematopoietic neoplasms in mice
Kogan, S. C., Ward, J. M., Anver, M. R., Berman, J. J., Brayton, C., Cardiff, R. D., Carter, J. S., de Coronado, S., Downing, J. R., Fredrickson, T. N., et al. (2002) · Blood · doi:10.1182/blood.v100.1.238 · Cited by 418
Requirement for CD44 in homing and engraftment of BCR-ABL-expressing leukemic stem cells
Krause, D. S., Lazarides, K., von Andrian, U. H., & Van Etten, R. A. (2006) · Nature Medicine · doi:10.1038/nm1489 · Cited by 349
Rac GTPases differentially integrate signals regulating hematopoietic stem cell localization
Cancelas, J. A., Lee, A. W., Prabhakar, R., Stringer, K. F., Zheng, Y., & Williams, D. A. (2005) · Nature Medicine · doi:10.1038/nm1274 · Cited by 278
Self-citation
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PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells
Neviani, P., Harb, J. G., Oaks, J. J., Santhanam, R., Walker, C. J., Ellis, J. J., Ferenchak, G. J., Dorrance, A. M., Paisie, C. A., Eiring, A. M., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci68951 · Cited by 231
Nieborowska-Skorska, M., Kopinski, P. K., Ray, R., Hoser, G., Ngaba, D., Flis, S., Cramer, K., Reddy, M. M., Koptyra, M., Penserga, T., et al. (2012) · Blood · doi:10.1182/blood-2011-10-385658 · Cited by 177
Self-citationRho GTPases modulate malignant transformation of tumor cells
Orgaz, J. L., Herráiz, C., & Sanz‐Moreno, V. (2014) · Small GTPases · doi:10.4161/sgtp.29019 · Cited by 195
O’Hare, T., Deininger, M. W., Eide, C. A., Clackson, T., & Druker, B. J. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-3314 · Cited by 150
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Metadata
- Authors
- Sengupta, A., Arnett, J., Dunn, S., Williams, D. A., & Cancelas, J. A.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- University of Cincinnati (US)
- Boston Children's Hospital (US)
- Stem Cell Biology Program, Division of Experimental Hematology & Cancer Biology, Cincinnati Children's Hospital Medical Center, OH;
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2010-07-08
- Volume
- 116
- Issue
- 1
- Pages
- 81-84
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC2904584
- OpenAlex
- W2077305244
- Cited by
- 52
- References
- 19
- Citations by year
- 2022: 1 · 2021: 2 · 2020: 3 · 2019: 4 · 2018: 4 · 2017: 1 · 2016: 5 · 2015: 5 · 2014: 4 · 2013: 4 · 2012: 8
- FWCI
- 4.51
- Type
- journal article
- Language
- en
- Open access
- green
- pmc.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL087159)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK062757)
- Topics
- Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Keywords
- BCR-ABL, chronic myeloid leukemia, leukemia stem cells, hematopoietic stem cells, myeloproliferative neoplasms, apoptosis, cell proliferation, Rac1, hematopoietic microenvironment
- MeSH terms
- T-Cell Acute Lymphocytic Leukemia Protein 1, RAC2 GTP-Binding Protein, Animals, Cell Adhesion, Cell Movement, Female, Flow Cytometry, Hematopoietic Stem Cells, Male, Mice, Inbred C57BL, Mice, Transgenic, Proto-Oncogene Proteins, Neoplastic Stem Cells, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Fusion Proteins, bcr-abl, Mice, Knockout, rac GTP-Binding Proteins, Cell Proliferation, Mice, Basic Helix-Loop-Helix Proteins, Kaplan-Meier Estimate
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- Sengupta, A., Arnett, J., Dunn, S., Williams, D. A., & Cancelas, J. A. (2010). Rac2 GTPase deficiency depletes BCR-ABL+ leukemic stem cells and progenitors in vivo. Blood. https://doi.org/10.1182/blood-2009-10-247437
