Increased LEF1 protein levels and isoform switching drive cell proliferation in chronic lymphocytic leukemia

The transcription factor lymphoid enhancer-binding factor 1 (LEF1) is aberrantly expressed across all subtypes and stages of chronic lymphocytic leukemia (CLL), yet the molecular mechanisms underlying its contribution to CLL pathogenesis remain poorly defined. Here, we conducted a comprehensive mechanistic dissection of LEF1 function in CLL using extensive functional analyses of patient-derived samples. We identified that, although LEF1 messenger RNA levels remain stable, patients with clinically aggressive disease show elevated LEF1 protein levels due to enhanced protein stability. LEF1 protein abundance is selectively modulated by lymph node-derived stimuli, including T-cell interactions and B-cell receptor signaling. Importantly, we uncovered a dual, context-dependent role for LEF1 that is determined by its protein levels. Low LEF1 protein, characteristic of indolent disease, supports B-cell activation, whereas increased protein abundance in aggressive disease promotes proliferation through the binding and induction of cell cycle and metabolic gene networks. We further showed that LEF1 exon 6 skipping is enriched in proliferative and aggressive CLL. Both in vitro and in vivo experiments revealed that LEF1-driven proliferation is mediated by these short, alternative spliced isoforms. Although all LEF1 isoforms bind to a core set of proliferation- and activation-related genes, they induce distinct transcriptional programs; full-length LEF1 promotes a quiescence gene signature and limits leukemic growth, whereas exon 6-skipping isoforms drive proliferation. Our findings establish LEF1 as an oncogenic transcription factor in CLL whose biological and clinical effects are modulated posttranscriptionally by both protein abundance and isoform composition.

Authors

Institutions

Publication Details

Journal
Blood
Published
2025-09-22
DOI
https://doi.org/10.1182/blood.2025030129
Citations
1
Primary Topic
Chronic Lymphocytic Leukemia Research
Type
article
Field-Weighted Citation Impact
1.63
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Increased LEF1 protein levels and isoform switching drive cell proliferation in chronic lymphocytic leukemia

Sophie A. Herbst, Raúl F. Pérez, Guadalupe Espadas, Martí Duran‐Ferrer et al.
1 citations
Blood
Chronic Lymphocytic Leukemia Research
1.63
article

Increased LEF1 protein levels and isoform switching drive cell proliferation in chronic lymphocytic leukemia

Sophie A. Herbst, Raúl F. Pérez, Guadalupe Espadas, Martí Duran‐Ferrer, Judith Mateos-Jaimez, Jérôme Paggetti, José I. Martı́n-Subero, Anna Vidal Crespo, Elı́as Campo, Eduard Sabidó, Etienne Moussay, Miguel Alcoceba, Ferran Nadeu, Sascha Dietrich, Stella Charalampopoulou, Anne Largeot, Alba Maiqués-Díaz, Ingo Ringshausen, Miguel Bastos, Dolors Colomer, Liska Caviedes-Cárdenas, Vicente Chapaprieta, Víctor Jiménez-Martínez
article en
1 citations

Abstract

The transcription factor lymphoid enhancer-binding factor 1 (LEF1) is aberrantly expressed across all subtypes and stages of chronic lymphocytic leukemia (CLL), yet the molecular mechanisms underlying its contribution to CLL pathogenesis remain poorly defined. Here, we conducted a comprehensive mechanistic dissection of LEF1 function in CLL using extensive functional analyses of patient-derived samples. We identified that, although LEF1 messenger RNA levels remain stable, patients with clinically aggressive disease show elevated LEF1 protein levels due to enhanced protein stability. LEF1 protein abundance is selectively modulated by lymph node-derived stimuli, including T-cell interactions and B-cell receptor signaling. Importantly, we uncovered a dual, context-dependent role for LEF1 that is determined by its protein levels. Low LEF1 protein, characteristic of indolent disease, supports B-cell activation, whereas increased protein abundance in aggressive disease promotes proliferation through the binding and induction of cell cycle and metabolic gene networks. We further showed that LEF1 exon 6 skipping is enriched in proliferative and aggressive CLL. Both in vitro and in vivo experiments revealed that LEF1-driven proliferation is mediated by these short, alternative spliced isoforms. Although all LEF1 isoforms bind to a core set of proliferation- and activation-related genes, they induce distinct transcriptional programs; full-length LEF1 promotes a quiescence gene signature and limits leukemic growth, whereas exon 6-skipping isoforms drive proliferation. Our findings establish LEF1 as an oncogenic transcription factor in CLL whose biological and clinical effects are modulated posttranscriptionally by both protein abundance and isoform composition.

BloodVol. 146(26)
Institució Catalana de Recerca i Estudis Avançats (ES), Universidad Complutense de Madrid (ES), Universitat Pompeu Fabra (ES), Universidad de Salamanca (ES), Heidelberg University (DE), University Hospital Heidelberg (DE), London Cancer (GB), Düsseldorf University Hospital (DE), Luxembourg Institute of Health (LU), Hospital Clínic de Barcelona (ES), Instituto de Investigación Biomédica de Salamanca (ES), Centre for Genomic Regulation (ES), Centro de Investigación del Cáncer (ES), CRUK Lung Cancer Centre of Excellence (GB), Centro de Investigación Biomédica en Red de Cáncer (ES), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Heinrich Heine University Düsseldorf (DE), University College London (GB), Universitat de Barcelona (ES)
Openalex Percentile: Top 13%
Chronic Lymphocytic Leukemia Research
1.63
DOISourceOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.