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Deletion of murine Rhoh leads to de-repression of Bcl-6 via decreased KAISO levels and accelerates a malignancy phenotype in a murine model of lymphoma
Open accessAbstract
RHOH/TFF, a member of the RAS GTPase super family, has important functions in lymphopoiesis and proximal T cell receptor signalling and has been implicated in a variety of leukaemias and lymphomas. RHOH was initially identified as a translocation partner with BCL-6 in non-Hodgkin lymphoma (NHL), and aberrant somatic hypermutation (SHM) in the 5ʹ untranslated region of the RHOH gene has also been detected in Diffuse Large B-Cell Lymphoma (DLBCL). Recent data suggest a correlation between RhoH expression and disease progression in Acute Myeloid Leukaemia (AML). However, the effects of RHOH mutations and translocations on RhoH expression and malignant transformation remain unknown. We found that aged Rhoh−/− (KO) mice had shortened lifespans and developed B cell derived splenomegaly with an increased Bcl-6 expression profile in splenocytes. We utilized a murine model of Bcl-6 driven DLBCL to further explore the role of RhoH in malignant behaviour by crossing RhohKO mice with Iµ-HABcl-6 transgenic (Bcl-6Tg) mice. The loss of Rhoh in Bcl-6Tg mice led to a more rapid disease progression. Mechanistically, we demonstrated that deletion of Rhoh in these murine lymphoma cells was associated with decreased levels of the RhoH binding partner KAISO, a dual-specific Zinc finger transcription factor, de-repression of KAISO target Bcl-6, and downregulation of the BCL-6 target Blimp-1. Re-expression of RhoH in RhohKOBcl-6Tg lymphoma cell lines reversed these changes in expression profile and reduced proliferation of lymphoma cells in vitro. These findings suggest a previously unidentified regulatory role of RhoH in the proliferation of tumour cells via altered BCL-6 expression. (250)
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TL;DR
Deletion of murine *Rhoh* shortens lifespan, expands B cells, and accelerates Bcl-6-driven lymphoma in an Iµ-HABcl-6 transgenic model. Mechanistically, loss of RhoH reduces KAISO, de-represses Bcl-6, lowers BLIMP-1, and increases lymphoma cell proliferation, effects partly reversed by RhoH re-expression.
Key findings
- Aged *Rhoh* KO mice had shortened median survival versus WT (562 vs 692 days, p < 0.01), splenomegaly, expanded CD19+ B cells, and increased BCL-6 and Ki-67 in splenocytes.
- In the Bcl-6 Tg lymphoma model, KOTg mice died faster than WTTg mice (median survival 359 vs 492 days; WTnTg 718 days), with more severe splenomegaly and significantly increased Ki-67+ lymphoma cells, but no significant difference in Cleaved Caspase-3 apoptosis.
- RhoH interacted with KAISO; KOTg lymphoma cells showed decreased KAISO, especially nuclear KAISO, and ChIP-qPCR showed KAISO enrichment at Bcl-6 promoter regions R1 (bp −900~−450) and R3 (bp +2165~+2423) after RhoH re-expression.
- RhoH re-expression reduced KOTg lymphoma cell proliferation at 7 days (8.6×10^6 ± 1.9×10^5 vs 5.9×10^6 ± 1.9×10^5 cells; KOTg-Control vs KOTg-RhoH, p < 0.05), and BLIMP-1 over-expression also reduced proliferation at 6 days (1.3×10^6 ± 7.4×10^4 vs 1.8×10^5 ± 1.0×10^4 cells; KOTg-Control vs KOTg-BLIMP-1, p < 0.001).
Methods
- Murine genetics and phenotyping: *Rhoh* KO and Iµ-HABcl-6 Bcl-6 Tg mice were crossed to generate WTTg and KOTg cohorts; survival, spleen weights, histology, immunohistochemistry, and flow cytometry were assessed.
- Cell and molecular assays: CD19+ splenic lymphoma/malignant B cell lines were established, transduced with HA-RhoH or FLAG-BLIMP-1 retroviral vectors, and analyzed by immunoprecipitation, immunoblotting, immunofluorescence, ChIP-qPCR, qRT-PCR, and in vitro proliferation assays.
- Statistics: unpaired two-tailed Student’s t-test, Kaplan-Meier survival curves with log-rank test, and p < 0.05 significance threshold.
Limitations
- Stated: the authors note that additional studies in human lymphoma cells interrogating RhoH and KAISO expression would be informative, and that the role of RhoH in hematopoietic transformation remains incompletely understood.
- Evident: the mechanistic and disease-progression conclusions rely on murine models and derived cell lines, with no human patient validation reported in this paper.
- Evident: several mechanistic findings depend on retroviral re-expression/over-expression in cell lines, and the in vivo lymphoma model uses a single Bcl-6-driven transgenic system.
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In the paper
“Reexpression of RhoH in Rhoh KO Bcl-6 Tg (KOTg) lymphoma cell lines increases nuclear KAISO levels, decreases BCL-6 protein expression, and leads to reduced proliferation of lymphoma cells.”
§ Deletion of murine Rhoh leads to de-repression of Bcl-6 via decreased KAISO levels and accelerates a malignancy phenotype in a murine model of lymphoma > Discussion
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In the paper
“HA-tagged RhoH bound to KAISO in RhoHtransduced Rhoh KO B cells, confirming the interaction of KAISO and RhoH in those cells using coimmunoprecipitation.”
§ Deletion of murine Rhoh leads to de-repression of Bcl-6 via decreased KAISO levels and accelerates a malignancy phenotype in a murine model of lymphoma > RhoH interacts with KAISO and affects the cellular content of KAISO, expression of its target Bcl-6, and downregulation of the BCL-6 target Blimp-1 in lymphoma cells
boostedstates an association- Asserted: passes — The authors put it forward as true.
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In the paper
“were uniformly and strongly positive for IRF4”
§ Deletion of murine Rhoh leads to de-repression of Bcl-6 via decreased KAISO levels and accelerates a malignancy phenotype in a murine model of lymphoma > Rhoh KO Bcl-6 Tg mice show more rapid disease progression in a murine model of lymphoma with increased proliferation of lymphoma cells
boosted- Asserted: passes — The authors put it forward as true.
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- 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
“The percentage of Ki-67-positive cells was significantly increased in KOTg splenic lymphoma cells compared to WTTg lymphoma controls”
§ Deletion of murine Rhoh leads to de-repression of Bcl-6 via decreased KAISO levels and accelerates a malignancy phenotype in a murine model of lymphoma > Rhoh KO Bcl-6 Tg mice show more rapid disease progression in a murine model of lymphoma with increased proliferation of lymphoma cells
plainstates an association- Asserted: passes — The authors put it forward as true.
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In the paper
“significantly increased percentage of Ki-67 + cells in the KO mouse spleen compared to the WT control”
§ Deletion of murine Rhoh leads to de-repression of Bcl-6 via decreased KAISO levels and accelerates a malignancy phenotype in a murine model of lymphoma > Rhoh -/-(KO) mice have shortened lifespans and splenomegaly due to an expansion of proliferating B cells with increased BCL-6 expression
plainstates an association- Asserted: passes — The authors put it forward as true.
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Citations
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Self-citationThe p120 catenin partner Kaiso is a DNA methylation-dependent transcriptional repressor
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Direct Repression of prdm1 by Bcl-6 Inhibits Plasmacytic Differentiation
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The Catenin p120 ctn Interacts with Kaiso, a Novel BTB/POZ Domain Zinc Finger Transcription Factor
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Research works printed but not linked: 1
- Dallery E, 1995, Oncogene, 10, 2171
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Molecular basis and current insights of atypical Rho small GTPase in cancer
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Shelley, C. S., Galiègue‐Zouitina, S., Andritsos, L. A., Epperla, N., & Troussard, X. (2024) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428194.2024.2438800
Metadata
- Authors
- Horiguchi, H., Xu, H., Duvert, B., Ciuculescu, F., Yao, Q., Sinha, A., McGuinness, M., Harris, C., Brendel, C., Troeger, A., Chiarle, R., & Williams, D. A.
- Affiliations
- Boston Children's Hospital (US)
- BasepairTech, New York, NY, USA
- University Hospital Regensburg (DE)
- Corresponding author
- Williams, David A.
- ORCID
- Venue
- Small GTPases
- Publisher
- Informa UK Limited
- Published
- 2022-01-05
- Volume
- 13
- Issue
- 1
- Pages
- 267-281
- ISSN
- 2154-1248 (ISSN-L)
- 2154-1256
- PMC
- PMC8741284
- OpenAlex
- W4206840290
- Semantic Scholar
- bc006b1b01145be8179863f073b67a2b19aa8674
- Cited by
- 3
- References
- 37
- Citations by year
- 2024: 3
- FWCI
- 0.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Small GTPases (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- RhoH, BCL6, Kaiso, Blimp-1, diffuse large B-cell lymphoma, lymphoma progression, zinc finger transcription factor, lymphoma cell proliferation, Rho GTPases
- MeSH terms
- Animals, Cell Transformation, Neoplastic, Disease Models, Animal, Lymphoma, Mice, Transgenic, Phenotype, Transcription Factors, Mice, Knockout, rho GTP-Binding Proteins, Mice, Proto-Oncogene Proteins c-bcl-6
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