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RhoH is critical for cell-microenvironment interactions in chronic lymphocytic leukemia in mice and humans
Open accessAbstract
Trafficking of B-cell chronic lymphocytic leukemia (CLL) cells to the bone marrow and interaction with supporting stromal cells mediates important survival and proliferation signals. Previous studies have demonstrated that deletion of Rhoh led to a delayed disease onset in a murine model of CLL. Here we assessed the impact of RhoH on homing, migration, and cell-contact dependent interactions of CLL cells. Rhoh−/− CLL cells exhibited reduced marrow homing and subsequent engraftment. In vitro migration toward the chemokines CXCL12 and CXCL13 and cell-cell interactions between Rhoh−/− CLL cells and the supporting microenvironment was reduced. In the absence of RhoH the distribution of phosphorylated focal adhesion kinase, a protein known to coordinate activation of the Rho GTPases RhoA and Rac, appeared less polarized in chemokine-stimulated Rhoh−/− CLL cells, and activation and localization of RhoA and Rac was dysregulated leading to defective integrin function. These findings in the Rhoh−/− CLL cells were subsequently demonstrated to closely resemble changes in GTPase activation observed in human CLL samples after in vitro and in vivo treatment with lenalidomide, an agent with known influence on microenvironment protection, and suggest that RhoH plays a critical role in prosurvival CLL cell-cell and cell-microenvironment interactions with this agent.
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TL;DR
RhoH deficiency in a murine CLL model reduced bone marrow homing, chemokine-directed migration, and interaction with nurse-like cells, with dysregulated RhoA/Rac and FAK signaling. Lenalidomide treatment of primary human CLL cells produced similar changes, suggesting RhoH is important for CLL cell–microenvironment interactions.
Key findings
- Rhoh−/− CLL cells showed reduced BM homing 16 hours after injection (1.7 × 10−3% ± 0.23 vs 3 × 10−3% ± 0.17; Rhoh−/− vs WT, P = .004) and reduced blood disease burden after transplantation (1.2 ± 0.3 vs 13.1 ± 3 K/μL; P = .004), with prolonged survival (P = .014).
- In vitro migration was reduced toward CXCL12 (1.7% ± 0.3 vs 7.3% ± 0.4; P < .001), toward CXCL12 with ICAM-1 (19.4% ± 5 vs 44.6% ± 1.6; P = .02), and toward CXCL13 (9.5% ± 1.3 vs 20.0% ± 1.6; P < .01).
- Rhoh−/− CLL cells interacted less with NLCs from spleen (7 ± 1.7 vs 17 ± 1.3; P = .0001) and PB (2 ± 0.3 vs 16 ± 3; P = .001), while Mac-2+ cells were increased in Rhoh−/− spleens (46.7 ± 3.6 vs 20.8 ± 1.2; P = .004).
- Rhoh−/− CLL cells had increased baseline RhoA/Rac activation and no further activation after CXCL12/CXCL13; lenalidomide decreased RhoH and increased RhoA/Rac activity in human CLL samples, including in vivo (RhoH 0.44 ± 0.11 vs 0.29 ± 0.09, P = .004; RhoA 0.08 ± 0.02 vs 0.40 ± 0.05, P = .002; Rac 0.77 ± 0.08 vs 1.43 ± 0.36, P = .002).
Methods
- Murine Eμ-TCL1Tg;Rhoh+/+ and Eμ-TCL1Tg;Rhoh−/− CLL cells were used for in vivo homing and transplantation into nonirradiated Rag2−/−IL2γ−/− recipients, with flow cytometry identifying CD3−/CD5+/IgM+ CLL cells.
- In vitro assays included transwell chemotaxis toward CXCL12/CXCL13 with or without ICAM-1, NLC cultures, immunofluorescence for RhoA/Rac/pFAK, histology for Mac-2, and GTPase pull-down/Western blotting.
- Human PB CLL samples (> 90% CD19+CD5+ for in vitro studies) were treated with 0.5 μM lenalidomide or vehicle; paired samples from relapsed patients were obtained before and after 8 days of 2.5–5 mg/day lenalidomide in a phase 1 trial (NCT00466895), with GTPase activity assessed by pull-down/Western blot.
Limitations
- The paper states that the exact mechanism by which lenalidomide down-regulates RhoH remains unknown and is under investigation, and that more detailed work is needed on how decreased RhoH influences CLL migration.
- The paper notes that human CLL cells after cryopreservation had a low overall migratory response, and lenalidomide-treated samples showed only a trend toward reduced chemokine-induced migration (data not shown).
- Evident from the text: human lenalidomide findings rely on small samples (4 of 5 in vitro samples; 6 paired in vivo samples), and the causal link between RhoH loss and human CLL disease progression is inferred from murine and correlative human data rather than directly demonstrated.
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In the paper
“Eμ-TCL1Tg;Rhoh−/− mice were characterized by a significantly reduced number of CLL cells in the BM”
What the sources say
- Supportedcites [20] Sanchez-Aguilera, 2010, Involvement of RhoH GTPase in the development of B-cell chronic lymphocytic leukemia., Leukemia source
The Results section reports significantly lower leukemic burden in the bone marrow of six-month-old Eμ-TCL1Tg;Rhoh−/− mice than in Eμ-TCL1Tg;Rhoh+/+ mice (5.4-fold reduction, p < 0.05). The Methods define leukemic burden at each site as the number of CLL cells. (LLM, conf=0.95)
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In the paper
“In the absence of RhoH the distribution of phosphorylated focal adhesion kinase, a protein known to coordinate activation of the Rho GTPases RhoA and Rac, appeared less polarized in chemokine-stimulated Rhoh−/− CLL cells”
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In the paper
“Sixteen hours after injection of 20 to 25 × 106 CLL cells, significantly less Rhoh−/− CLL cells compared with WT CLL cells were detected in the BM (3 × 10−3 % ± 0.17 vs 1.7 × 10−3 % ± 0.23; WT vs Rhoh−/−, mean ± SEM, respectively, MWU test, P = .004; Figure 1A).”
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In the paper
“Directed migration of Eμ-TCL1Tg;Rhoh−/− CLL cells toward CXCL12 was significantly reduced compared with Eμ-TCL1Tg;WT CLL cells (1.7% ± 0.3 vs 7.3% ± 0.4; Eμ-TCL1Tg;Rhoh−/− vs Eμ-TCL1Tg;WT, P < .001; Figure 3A).”
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“Despite an increased spontaneous apoptosis rate (supplemental Figure 1, available on the Blood Web site; see the Supplemental Materials link at the top of the online article), the number of Rhoh−/− CLL cells remaining in the PB was slightly increased (Figure 1B)”
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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
“Disease progression is attenuated in a Rhoh ؊/؊ mouse model of chronic lymphocytic leukemia”
From A Unique Carboxyl-terminal Insert Domain in the Hematopoietic-specific, GTPase-deficient Rho GTPase RhoH Regulates Post-translational Processing (2013) · cites this paper as [13]
In the citing paper
“treatment of primary human chronic lymphocytic leukemia cells with Lenalidomide results in reduced RhoH protein levels.”
From A Unique Carboxyl-terminal Insert Domain in the Hematopoietic-specific, GTPase-deficient Rho GTPase RhoH Regulates Post-translational Processing (2013) · cites this paper as [13]
In the citing paper
“We have also demonstrated that in a murine model of CLL, RhoH knock-out leads to delayed disease progression associated with reduced access of malignant cells to protective niches, which contributes to decreased CLL cell survival in vivo (12,13).”
From A Unique Carboxyl-terminal Insert Domain in the Hematopoietic-specific, GTPase-deficient Rho GTPase RhoH Regulates Post-translational Processing (2013) · cites this paper as [13]
In the citing paper
“We have also demonstrated that in a murine model of CLL, RhoH knock-out leads to delayed disease progression associated with reduced access of malignant cells to protective niches, which contributes to decreased CLL cell survival in vivo (12,13).”
From A Unique Carboxyl-terminal Insert Domain in the Hematopoietic-specific, GTPase-deficient Rho GTPase RhoH Regulates Post-translational Processing (2013) · cites this paper as [13]
In the citing paper
“Furthermore, Lenalidomide, which is effective in treatment of CLL in vivo and in vitro, results in decreased RhoH expression levels in primary CLL cells (13).”
From A Unique Carboxyl-terminal Insert Domain in the Hematopoietic-specific, GTPase-deficient Rho GTPase RhoH Regulates Post-translational Processing (2013) · cites this paper as [13]
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Citations
Cites
Cell Migration: Integrating Signals from Front to Back
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Research works printed but not linked: 1
- Chae, 2010, RhoH regulates subcellular localization of ZAP-70 and Lck in T cell receptor signaling., PLoS One, 5, e13970, 10.1371/journal.pone.0013970 · DOI · Paper page
Cited by
Rho GTPases: Regulation and roles in cancer cell biology
Haga, R. B., & Ridley, A. J. (2016) · Small GTPases · doi:10.1080/21541248.2016.1232583 · Cited by 576
Burger, J. A., & Gribben, J. G. (2013) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2013.08.011 · Cited by 300
ten Hacken, E., & Burger, J. A. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2015.07.009 · Cited by 239
Reinart, N., Nguyen, P., Bouças, J., Rosen, N., Kvasnicka, H. M., Heukamp, L. C., Rudolph, C., Ristovska, V., Velmans, T., Mueller, C., et al. (2012) · Blood · doi:10.1182/blood-2012-05-431452 · Cited by 109
Amé-Thomas, P., & Tarte, K. (2013) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2013.08.001 · Cited by 106
Metadata
- Authors
- Troeger, A., Johnson, A. J., Wood, J., Blum, W. G., Andritsos, L. A., Byrd, J. C., & Williams, D. A.
- Affiliations
- Boston Children's Hospital (US)
- The Ohio State University (US)
- Division of Hematology, Department of Medicine, and
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2012-05-17
- Volume
- 119
- Issue
- 20
- Pages
- 4708-4718
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC3367874
- OpenAlex
- W2094795565
- Semantic Scholar
- 30a2a6727ee05bf77c3b17b5bc2f828e340e3ad2
- Cited by
- 55
- References
- 56
- Citations by year
- 2026: 1 · 2024: 3 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 3 · 2019: 2 · 2018: 4 · 2017: 4 · 2016: 3 · 2015: 5 · 2014: 9 · 2013: 12 · 2012: 2
- FWCI
- 5.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- Funders
- National Institutes of Health (U54TR001005)
- National Cancer Institute (P01CA095426, P50CA140158, R01CA113969, P01CA081534, K12CA133250)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Hematology › Chronic Lymphocytic Leukemia Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and Retrovirus Studies
- Keywords
- RhoH, chronic lymphocytic leukemia, cell-microenvironment interactions, bone marrow homing, cell migration, CXCL12, CXCL13, focal adhesion kinase, RhoA, Rac, integrin function, lenalidomide, stromal cells, Rho GTPases
- MeSH terms
- Animals, Bone Marrow, Cell Communication, Cells, Cultured, Chemotaxis, Leukocyte, Humans, Mice, Inbred C57BL, Spleen, Transcription Factors, Leukemia, Lymphocytic, Chronic, B-Cell, Mice, Knockout, rho GTP-Binding Proteins, Mice, Chemokine CXCL12, Chemokine CXCL13, Tumor Microenvironment
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- Troeger, A., Johnson, A. J., Wood, J., Blum, W. G., Andritsos, L. A., Byrd, J. C., & Williams, D. A. (2012). RhoH is critical for cell-microenvironment interactions in chronic lymphocytic leukemia in mice and humans. Blood. https://doi.org/10.1182/blood-2011-12-395939
