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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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In the paper
“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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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
“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
plainstates an association- Asserted: passes — The authors put it forward as true.
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In the paper
“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
plainstates a causen = 2- Asserted: passes — The authors put it forward as true.
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In the paper
“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
plainstates a cause- Asserted: passes — The authors put it forward as true.
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In the paper
“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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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
About these checks
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.
A language model drew the claims from the paper on 2026-11-12, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-12 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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