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Rac Guanosine Triphosphatases Represent Integrating Molecular Therapeutic Targets for BCR-ABL-Induced Myeloproliferative Disease
Open accessAbstract
Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disease (MPD) initiated by expression of the p210-BCR-ABL fusion protein. We demonstrate in a murine model of p210-BCR-ABL-induced MPD that gene targeting of Rac1 and Rac2 significantly delays or abrogates disease development. Attenuation of the disease phenotype is associated with severely diminished p210-BCR-ABL-induced downstream signaling in primary hematopoietic cells. We utilize NSC23766, a small molecule antagonist of Rac activation, to validate biochemically and functionally Rac as a molecular target in both a relevant animal model and in primary human CML cells in vitro and in a xenograft model in vivo, including in Imatinib-resistant p210-BCR-ABL disease. These data demonstrate that Rac is an additional therapeutic target in p210-BCR-ABL-mediated MPD.
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TL;DR
In a murine p210-BCR-ABL myeloproliferative disease model, combined Rac1/Rac2 deficiency significantly delays or abrogates disease, and the Rac inhibitor NSC23766 impairs p210-BCR-ABL-driven proliferation and leukemogenesis, including Imatinib-resistant T315I disease. These data identify Rac GTPases as integrating therapeutic targets in p210-BCR-ABL-mediated MPD.
Key findings
- Rac1, Rac2, and to a lesser degree Rac3 were hyperactivated in CD34+ cells from two chronic-phase CML patients; p210-BCR-ABL expression in murine LDBM cells led to a >2-fold increase in GTP-bound Rac.
- Mice transplanted with p210-BCR-ABL-expressing Rac1^D/D;Rac2^-/- cells showed significantly prolonged survival versus WT and Rac1^D/D mice (p < 0.001), with nearly 50% alive at 100 days posttransplant; Rac2^-/- survival was intermediate and also significantly longer than WT/Rac1^D/D (p < 0.001).
- NSC23766 inhibited p210-BCR-ABL-induced proliferation dose-dependently; in Imatinib-resistant Ba/F3 T315I-p210-BCR-ABL cells, up to 3 µM Imatinib alone caused <10% inhibition, whereas NSC23766 alone or with Imatinib caused >90% inhibition.
- In vivo, NSC23766 significantly increased survival of mice with p210-BCR-ABL-induced disease (p < 0.01), and in NOD/SCID mice transplanted with human chronic-phase CML CD34+ cells, NSC23766 induced ~85% reduction in human CML by 17 days posttransplant.
Methods
- Murine retroviral p210-BCR-ABL MPD model using 5-FU-treated LDBM cells from Cre-Tg+;WT, Rac1^flox/flox, Rac2^-/-, and Rac1^flox/flox;Rac2^-/- mice; EGFP+ transduced cells were transplanted into irradiated C57Bl/6 mice, with polyI:C-induced Rac1 deletion 10 days posttransplant.
- Analyses included survival curves, blood counts/differentials, LAM-PCR and Southern blot for clonality, PBD pull-down assays for Rac activation, immunoblotting for ERK/JNK/p38/Akt/STAT5/CrkL phosphorylation, proliferation assays, and CFU-GM assays.
- Human specimens included CD34+ peripheral blood CML cells from two patients and normal BM; NSC23766 was tested in vitro, in Ba/F3 T315I-p210-BCR-ABL cells, and in vivo via osmotic pumps in murine and NOD/SCID xenograft models. Statistics used unpaired Student’s t test and log rank test for survival, with p < 0.05 considered significant.
Limitations
- The paper does not include a formal limitations section.
- Evident from the text: NSC23766 inhibition of Rac activation is reversible and less complete than genetic deletion, and it is described as a first-generation small molecule inhibitor.
- Evident from the text: human primary CML validation used cells from two patients, and the role of Rac3 in hematopoiesis/disease is not fully defined; the authors state studies are underway using Rac3^-/- mice bred into the Rac1^flox/flox;Rac2^-/- line.
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“We demonstrate in a murine model of p210-BCR-ABL-induced MPD that gene targeting of Rac1 and Rac2 significantly delays or abrogates disease development.”
§ Rac Guanosine Triphosphatases Represent Integrating Molecular Therapeutic Targets for BCR-ABL-Induced Myeloproliferative Disease > Abstract
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In the paper
“Attenuation of the disease phenotype is associated with severely diminished p210-BCR-ABL-induced downstream signaling in primary hematopoietic cells.”
§ Rac Guanosine Triphosphatases Represent Integrating Molecular Therapeutic Targets for BCR-ABL-Induced Myeloproliferative Disease > Abstract
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“As shown in Figure 6B, compared to the PBS-treated control mice, NSC23766 induced $85% reduction in human CML by 17 days posttransplant.”
§ Rac Guanosine Triphosphatases Represent Integrating Molecular Therapeutic Targets for BCR-ABL-Induced Myeloproliferative Disease > Rac Is a Molecular Target in p210-BCR-ABL-Expressing Cells
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“that we have found to inhibit Rac1, Rac2, and Rac3 in BCR-ABL-transduced LDBM cells (see Figure S2).”
§ Rac Guanosine Triphosphatases Represent Integrating Molecular Therapeutic Targets for BCR-ABL-Induced Myeloproliferative Disease > Rac Is a Molecular Target in p210-BCR-ABL-Expressing Cells
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“EGFP + cells in the spleen and BM of all p210-BCR-ABLtransplanted WT, Rac1 D/D , and Rac2 À/À recipient mice were uniformly Gr-1 + /Mac-1 + (Table S2).”
§ Rac Guanosine Triphosphatases Represent Integrating Molecular Therapeutic Targets for BCR-ABL-Induced Myeloproliferative Disease > Cancer Cell
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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
“We recently identified the Rac GTPases as molecular targets in BCR-ABL-induced myeloproliferative disease (2, 3).”
From Rac guanosine triphosphatases represent a potential target in AML (2008) · cites this paper as [3]
In the citing paper
“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.”
From Rac2 GTPase deficiency depletes BCR-ABL+ leukemic stem cells and progenitors in vivo (2010) · cites this paper as [11]
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 [32]
In the citing paper
“inhibition of RAC activity has been proven a successful strategy to target primary human AML and CML cells in vitro and in vivo [29,32,33].”
From Mitochondrial Dysfunction in Human Leukemic Stem/Progenitor Cells upon Loss of RAC2 (2015) · cites this paper as [32]
In the citing paper
“This is in agreement with the previous reports from murine models, in which loss of Rac2 prevented the development of BCR-ABL-initiated leukemia by increasing apoptosis of LSCs, rather that altering their interactions with the microenvironment [32].”
From Mitochondrial Dysfunction in Human Leukemic Stem/Progenitor Cells upon Loss of RAC2 (2015) · cites this paper as [32]
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In the paper
§ Rac Guanosine Triphosphatases Represent Integrating Molecular Therapeutic Targets for BCR-ABL-Induced Myeloproliferative Disease > Generation of Rac1-Deficient Hematopoietic Cells
“For NOD/SCID mice, mice were transplanted with a total of 10 3 10 6 CD34 + cells per mouse and pumps were implanted on day +16 posttransplantation.”
§ Rac Guanosine Triphosphatases Represent Integrating Molecular Therapeutic Targets for BCR-ABL-Induced Myeloproliferative Disease > Supplemental Data
“Fifteen days posttransplant, Alzet osmotic pumps containing either NSC23766 (2 pumps, 75 mM NSC23766 per pump) or PBS (1 pump) were surgically implanted into the animals.”
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Self-citation
Metadata
- Authors
- Thomas, E. K., Cancelas, J. A., Chae, H.-D., Cox, A. D., Keller, P. J., Perrotti, D., Neviani, P., Druker, B. J., Setchell, K. D. R., Zheng, Y., Harris, C. E., & Williams, D. A.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- University of North Carolina at Chapel Hill (US)
- The Ohio State University (US)
- Oregon Health & Science University (US)
- Corresponding author
- Williams, David A.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2007-11
- Volume
- 12
- Issue
- 5
- Pages
- 467-478
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2058761715
- Semantic Scholar
- 52bdfdc2ce0a4ed69b00420a02a6360fab9ccaab
- Cited by
- 147
- References
- 58
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 5 · 2021: 7 · 2020: 5 · 2019: 3 · 2018: 11 · 2017: 10 · 2016: 6 · 2015: 11 · 2014: 8 · 2013: 11 · 2012: 14
- FWCI
- 6.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- U.S. Department of Defense
- National Heart, Lung, and Blood Institute (P01HL069974)
- National Cancer Institute (R01CA095512)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK062757)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD046387)
- Topics
- Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- Rac1, Rac2, BCR-ABL, chronic myeloid leukemia, myeloproliferative neoplasms, p210 BCR-ABL, NSC23766, Rac inhibitor, imatinib resistance, therapeutic target, downstream signaling, xenograft models, gene targeting
- MeSH terms
- RAC2 GTP-Binding Protein, Aminoquinolines, Animals, Dose-Response Relationship, Drug, Hematopoietic Stem Cells, Humans, Myeloproliferative Disorders, Neoplasm Transplantation, Phenotype, Pyrimidines, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Gene Expression Regulation, Leukemic, Fusion Proteins, bcr-abl, Antigens, CD34, rac GTP-Binding Proteins, rac1 GTP-Binding Protein, Cell Line, Tumor, Mice
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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