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Pak and Rac GTPases promote oncogenic KIT–induced neoplasms
Open accessAbstract
An acquired somatic mutation at codon 816 in the KIT receptor tyrosine kinase is associated with poor prognosis in patients with systemic mastocytosis and acute myeloid leukemia (AML). Treatment of leukemic cells bearing this mutation with an allosteric inhibitor of p21-activated kinase (Pak) or its genetic inactivation results in growth repression due to enhanced apoptosis. Inhibition of the upstream effector Rac abrogates the oncogene-induced growth and activity of Pak. Although both Rac1 and Rac2 are constitutively activated via the guanine nucleotide exchange factor (GEF) Vav1, loss of Rac1 or Rac2 alone moderately corrected the growth of KIT-bearing leukemic cells, whereas the combined loss resulted in 75% growth repression. In vivo, the inhibition of Vav or Rac or Pak delayed the onset of myeloproliferative neoplasms (MPNs) and corrected the associated pathology in mice. To assess the role of Rac GEFs in oncogene-induced transformation, we used an inhibitor of Rac, EHop-016, which specifically targets Vav1 and found that EHop-016 was a potent inhibitor of human and murine leukemic cell growth. These studies identify Pak and Rac GTPases, including Vav1, as potential therapeutic targets in MPN and AML involving an oncogenic form of KIT.
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TL;DR
The Vav1/Rac/Pak pathway is constitutively activated downstream of oncogenic KITD814V/D816V and is required for transformation, and genetic or pharmacologic inhibition delays myeloproliferative neoplasms and prolongs survival. EHop-016 and Pak inhibition more potently repress growth of KIT-mutant leukemic cells than NSC23766.
Key findings
- KITD814V-bearing cells showed constitutive Vav1 phosphorylation and Rac1/Rac2 activation; Vav1 deficiency reduced ligand-independent growth by approximately 75%, Rac2 loss by approximately 50%, Rac1 loss only modestly (~10%–15%), and combined Rac1/Rac2 loss by approximately 75%.
- Dominant-negative RacN17 in KITD814V-bearing cells repressed growth and survival in vitro and in vivo prolonged survival, reduced peripheral blood WBC/neutrophil counts, reduced leukemic burden from up to 90% to approximately 20% EGFP-positive cells in PB/BM/spleen, and corrected spleen/lung pathology.
- EHop-016 inhibited growth of KITD816V-bearing HMC1.2 and Kasumi-1 cells at concentrations ~50-fold lower than NSC23766 in some cases; primary KITD816V-positive SM patient cells were more susceptible than KITD816V-negative samples. EHop-016 at 10 μM inhibited both Rac1 and Rac2, whereas 20 μM NSC23766 inhibited Rac1 but not Rac2.
- Pak was activated downstream of Vav1/Rac; dominant-negative PakK299R or IPA-3 repressed growth and survival, and KITD814V plus PakK299R mice survived beyond day 15 when all KITD814V-only mice died, with reduced spleen weight, PB counts, and tissue infiltration.
Methods
- Retroviral transduction of 32D myeloid cells and primary BM HSC/Ps with WT KIT or KITD814V, plus RacN17, PakK299R, activated Rac, or activated Pak; genetic models included Vav1−/−, Rac2−/−, and Mx1-Cre/Rac1flox/flox/Rac2−/− mice; human cells included HMC1.2, Kasumi-1, and primary SM patient samples.
- In vitro assays used [3H]thymidine incorporation for proliferation, annexin V/7-AAD for apoptosis, and Rac/Pak activation pulldown or Western blot; in vivo studies used syngeneic C3H/HeJ or lethally irradiated C57BL/6 transplant recipients, with survival, PB counts, flow cytometry, and histopathology.
- Statistics used mean ± SD unless otherwise stated, P < 0.05 as significant, and Kaplan-Meier log-rank analysis for survival.
Limitations
- Stated in the paper: whether other Pak isoforms contribute to leukemogenesis remains to be determined; the authors also state they have no direct evidence for which additional GEFs EHop-016 inhibits in oncogene KIT-bearing cells.
- Evident from the text: the in vivo Pak experiments used small cohorts (n = 3–4), and EHop-016’s mechanism in KIT-mutant cells is inferred partly from prior breast cancer cell line data rather than directly demonstrated in this system.
- Evident from the text: patient sample numbers and characteristics are not detailed, and the paper does not include a dedicated limitations section.
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“the activation of both Rac1 and Rac2 was reduced in KITD814V-bearing Vav1 -/-HSC/Ps.”
§ Pak and Rac GTPases promote oncogenic KIT-induced neoplasms > The GEF Vav1 regulates ligand-independent growth and Rac1 and Rac2 activation in oncogene KIT-bearing (KITD814V-bearing) cells.
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“mice transplanted with cells coexpressing KITD814V and RacN17 demonstrated a profound reduction in PB wbc and neutrophil (NE) counts.”
§ Pak and Rac GTPases promote oncogenic KIT-induced neoplasms > The GEF Vav1 regulates ligand-independent growth and Rac1 and Rac2 activation in oncogene KIT-bearing (KITD814V-bearing) cells.
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“Here, we show that KITD814V-bearing (mouse) and KITD816V-bearing (human) leukemic cells exhibit constitutive activation of Pak, Rac GTPases, and the GEF Vav1.”
§ Pak and Rac GTPases promote oncogenic KIT-induced neoplasms > Introduction
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“lack of Vav1 in these cells resulted in approximately 75% repression of ligand-independent growth (Figure 1B).”
§ Pak and Rac GTPases promote oncogenic KIT-induced neoplasms > The GEF Vav1 regulates ligand-independent growth and Rac1 and Rac2 activation in oncogene KIT-bearing (KITD814V-bearing) cells.
plainstates a cause- Asserted: passes — The authors put it forward as true.
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“mice transplanted with cells coexpressing KITD814V and RacN17 demonstrated only approximately 20% leukemic cells as determined by EGFP positivity in all three tissues examined.”
§ Pak and Rac GTPases promote oncogenic KIT-induced neoplasms > The GEF Vav1 regulates ligand-independent growth and Rac1 and Rac2 activation in oncogene KIT-bearing (KITD814V-bearing) cells.
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Claims other papers make about this one
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In the citing paper
“aberrant activations of RAC2, PAK1 and PI3K-AKT have been separately described17,22,41,42.”
From Gadd45g insufficiency drives the pathogenesis of myeloproliferative neoplasms (2024) · cites this paper as [17]
In the citing paper
“To identify possible proteins that directly interact with GADD45g, we performed GADD45g-interactome screening using immunoprecipitation (IP) followed by mass spectrometry (MS) in c-kit+ BM cells of wild-type mice, and identified RAC2, the only protein expressed exclusively in hematopoietic cells and promoting the progression of MPNs17, as a potential interacting protein (Supplementary Data 1).”
From Gadd45g insufficiency drives the pathogenesis of myeloproliferative neoplasms (2024) · cites this paper as [17]
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Metadata
- Authors
- Martin, H., Mali, R. S., Ma, P., Chatterjee, A., Ramdas, B., Sims, E., Munugalavadla, V., Ghosh, J., Mattingly, R. R., Visconte, V., Tiu, R. V., Vlaar, C. P., Dharmawardhane, S., & Kapur, R.
- Affiliations
- Indiana University Indianapolis (US)
- Genentech (US)
- Cleveland Clinic (US)
- University of Puerto Rico, Medical Sciences Campus (PR)
- Indiana University Bloomington (US)
- Corresponding author
- Kapur, Reuben
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2013-09-16
- Volume
- 123
- Issue
- 10
- Pages
- 4449-4463
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3784531
- OpenAlex
- W2124465965
- Semantic Scholar
- 04a7454232b373e5638010ec3764221778528956
- Cited by
- 45
- References
- 60
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 1 · 2023: 2 · 2022: 3 · 2021: 3 · 2020: 2 · 2019: 1 · 2018: 4 · 2017: 5 · 2016: 4 · 2015: 5 · 2014: 10
- FWCI
- 2.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- Funders
- American Cancer Society
- Riley Children's Foundation
- National Institutes of Health
- National Institute on Aging (F31AG040974)
- National Heart, Lung, and Blood Institute (R01HL077177, R01HL075816, T32HL007910)
- National Cancer Institute (R01CA134777)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Mast cells and histamine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- KIT, Rac1, Rac2, Vav1, p21-activated kinase, acute myeloid leukemia, myeloproliferative neoplasms, systemic mastocytosis, oncogene-induced transformation, apoptosis, therapeutic target
- MeSH terms
- Aminoquinolines, Animals, Antineoplastic Agents, Carbazoles, Cell Survival, Enzyme Activation, Humans, Mastocytosis, Mice, Inbred C3H, Mice, Inbred C57BL, Pyrimidines, Leukemia, Myeloid, Acute, Proto-Oncogene Proteins c-kit, Mutation, Missense, rac GTP-Binding Proteins, Xenograft Model Antitumor Assays, Cell Line, Tumor, Cell Proliferation, Mice, Proto-Oncogene Proteins c-vav, p21-Activated Kinases, Carcinogenesis
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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