ArticleBlood cancer discovery2023
In Vivo Modeling of CLL Transformation to Richter Syndrome Reveals Convergent Evolutionary Paths and Therapeutic Vulnerabilities.
Article in Blood cancer discovery, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 27 citations in OpenAlex.
- Strong constitutive NF-κB signaling in B cells drives SLL/CLL-like lymphomagenesis and overcomes microenvironmental dependencies.Leukemia · 2026Article
- Molecular Pathogenesis and Targeted Treatment of Richter Transformation.Biomedicines · 2026Review
- Safety and efficacy of the combination of copanlisib and nivolumab in patients with Richter's transformation or transformed non-Hodgkin lymphoma: results from a phase I trial.Haematologica · 2026Article
- Biology as vulnerability in follicular lymphoma: genetics, epigenetics, and immunogenetics.Blood · 2025Review
- Insights into PI3K/AKT signaling in B cell development and chronic lymphocytic leukemia.FEBS letters · 2025Review
- CLL to Richter syndrome: Integrating network strategies with experiments elucidating disease drivers and personalized therapies.Science advances · 2025Article
- Molecular Features Accompanying Richter's Transformation in Patients with Chronic Lymphocytic Leukemia.International journal of molecular sciences · 2025Review
- Complementary approaches define the metabolic features that accompany Richter syndrome transformation.Cellular and molecular life sciences : CMLS · 2025Article
- A question of TiME: how microenvironmental interactions shape response to immunotherapy in CLL and Richter Transformation.Frontiers in immunology · 2025Review
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- The molecular map of CLL and Richter's syndrome.Seminars in hematology · 2024Review
- Mouse models of chronic lymphocytic leukemia and Richter transformation: what we have learnt and what we are missing.Frontiers in immunology · 2024Review
- Richter transformation-is there light at the end of this tunnel?Hematology. American Society of Hematology. Education Program · 2023Review
- ZNF683 marks a CD8Cancer cell · 2023Article
- Review
Corrections and comments
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Authors and funding
40 authors at 13 institutions in 8 countries.
Funding
Abstract
Transformation to aggressive disease histologies generates formidable clinical challenges across cancers, but biological insights remain few. We modeled the genetic heterogeneity of chronic lymphocytic leukemia (CLL) through multiplexed in vivo CRISPR-Cas9 B-cell editing of recurrent CLL loss-of-function drivers in mice and recapitulated the process of transformation from indolent CLL into large cell lymphoma [i.e., Richter syndrome (RS)]. Evolutionary trajectories of 64 mice carrying diverse combinatorial gene assortments revealed coselection of mutations in Trp53, Mga, and Chd2 and the dual impact of clonal Mga/Chd2 mutations on E2F/MYC and interferon signaling dysregulation. Comparative human and murine RS analyses demonstrated tonic PI3K signaling as a key feature of transformed disease, with constitutive activation of the AKT and S6 kinases, downmodulation of the PTEN phosphatase, and convergent activation of MYC/PI3K transcriptional programs underlying enhanced sensitivity to MYC/mTOR/PI3K inhibition. This robust experimental system presents a unique framework to study lymphoid biology and therapy. SIGNIFICANCE: Mouse models reflective of the genetic complexity and heterogeneity of human tumors remain few, including those able to recapitulate transformation to aggressive disease histologies. Herein, we model CLL transformation into RS through multiplexed in vivo gene editing, providing key insight into the pathophysiology and therapeutic vulnerabilities of transformed disease. This article is highlighted in the In This Issue feature, p. 101.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.