Dual biological role and clinical impact of de novo chromatin activation in chronic lymphocytic leukemia

Previous studies have reported that chronic lymphocytic leukemia (CLL) shows a de novo chromatin activation pattern compared with normal B cells. Here, we explored whether the level of chromatin activation is related to the clinical behavior of CLL. We identified that, in some regulatory regions, increased de novo chromatin activation is linked to clinical progression, whereas, in other regions, it is associated with an indolent course. We next developed 2 prognostic scores for progressive and indolent disease, respectively, calculated a single score representing the balance between them, and further generated surrogate scores based on gene and protein expression of the target genes. The balance score outperformed the clinical impact of the 2 individual scores, because it seemed to capture the prognostic information provided by each of them. Biologically, CLLs with higher balance score showed increased activation of tumor necrosis factor alpha (TNF-α)/NF-κB and mTOR signaling pathways. Regulatory programs related to progression were predominantly activated in the lymph node microenvironment, whereas those linked to indolent disease appeared to be microenvironment independent. Finally, we thoroughly validated the balance score as a powerful and independent quantitative prognostic factor for time to first treatment across independent CLL cohorts and data modalities, such as chromatin, transcriptome, or proteome data. Our findings support the concept that de novo acquisition of chromatin changes in CLL cells plays a dual biological role, and the balance between proprogression and proindolence is a strong independent determinant of CLL prognosis.

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Publication Details

Journal
Blood
Published
2025-01-22
DOI
https://doi.org/10.1182/blood.2024025396
Citations
4
Primary Topic
Chronic Lymphocytic Leukemia Research
Type
article
Field-Weighted Citation Impact
6.50
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article

Dual biological role and clinical impact of de novo chromatin activation in chronic lymphocytic leukemia

Thorsten Zenz, Sophie A. Herbst, Guillem Clot, Romina Royo et al.
4 citations
Blood
Chronic Lymphocytic Leukemia Research
6.50
article

Dual biological role and clinical impact of de novo chromatin activation in chronic lymphocytic leukemia

Thorsten Zenz, Sophie A. Herbst, Guillem Clot, Romina Royo, Armando López‐Guillermo, Julio Delgado, Martí Duran‐Ferrer, Judith Mateos-Jaimez, José I. Martı́n-Subero, Anna Vidal Crespo, Neus Villamor, Laura Llaó Cid, Elı́as Campo, Núria Russiñol, Dean Bryant, Jonathan C. Strefford, Ferran Nadeu, Sascha Dietrich, Pablo Mozas, Stella Charalampopoulou, Alba Maiqués-Díaz, Juan A. Piñeyroa, Holger Heyn, Ramon Massoni-Badosa, Junyan Lu, Vicente Chapaprieta
article en
4 citations

Abstract

Previous studies have reported that chronic lymphocytic leukemia (CLL) shows a de novo chromatin activation pattern compared with normal B cells. Here, we explored whether the level of chromatin activation is related to the clinical behavior of CLL. We identified that, in some regulatory regions, increased de novo chromatin activation is linked to clinical progression, whereas, in other regions, it is associated with an indolent course. We next developed 2 prognostic scores for progressive and indolent disease, respectively, calculated a single score representing the balance between them, and further generated surrogate scores based on gene and protein expression of the target genes. The balance score outperformed the clinical impact of the 2 individual scores, because it seemed to capture the prognostic information provided by each of them. Biologically, CLLs with higher balance score showed increased activation of tumor necrosis factor alpha (TNF-α)/NF-κB and mTOR signaling pathways. Regulatory programs related to progression were predominantly activated in the lymph node microenvironment, whereas those linked to indolent disease appeared to be microenvironment independent. Finally, we thoroughly validated the balance score as a powerful and independent quantitative prognostic factor for time to first treatment across independent CLL cohorts and data modalities, such as chromatin, transcriptome, or proteome data. Our findings support the concept that de novo acquisition of chromatin changes in CLL cells plays a dual biological role, and the balance between proprogression and proindolence is a strong independent determinant of CLL prognosis.

BloodVol. 145(21)
Institució Catalana de Recerca i Estudis Avançats (ES), University of Zurich (CH), Cornell University (US), Heidelberg University (DE), Barcelona Supercomputing Center (ES), University Hospital Heidelberg (DE), Düsseldorf University Hospital (DE), Integrated Oncology (United States) (US), University Hospital of Zurich (CH), National Center for Tumor Diseases (DE), Hospital Clínic de Barcelona (ES), Intermolecular (United States) (US), European Molecular Biology Laboratory (DE), Centro Nacional de Análisis Genómico (ES), Fundació Clínic per a la Recerca Biomèdica (ES), Centro de Investigación Biomédica en Red de Cáncer (ES), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), University of Southampton (GB), Weill Cornell Medicine (US), Heinrich Heine University Düsseldorf (DE), Universitat de Barcelona (ES), Universitat Politècnica de Catalunya (ES)
Good health and well-being
Openalex Percentile: Top 4%
Chronic Lymphocytic Leukemia Research
6.50
DOISourceOpenAlex
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