IDH2 clonal hematopoiesis and IKAROS loss cooperate in a B-ALL subtype after lenalidomide therapy for multiple myeloma
Year: 2026
Type: article
Study design: Observational Study
Abstract: ABSTRACT: Lenalidomide, a maintenance treatment in multiple myeloma first-line therapy, increases the risk of secondary malignancies, including B-cell precursor acute lymphoblastic leukemia (B-ALL). We present a comprehensive molecular characterization of 57 patients with lenalidomide-associated B-ALL (LenB-ALL), revealing 3 mutational subgroups: (1) TP53mt (30%); (2) IDH2mt (p.R140Q) (23%); and (3) other, including NRAS/KRASmt. Remarkably, IDH2 R140Q mutations were highly enriched in LenB-ALL compared with those in primary B-ALL (P< .001). Furthermore, IKZF1 intragenic deletions, often subclonal and likely RAG recombinase-mediated, were observed in 54% (7/13) of IDH2mt patients with LenB-ALL. IDH2 mutations were not restricted to the leukemic clone: they persisted during measurable residual disease-negative remission and were identified in lymphoid as well as myeloid cell populations using fluorescence-activated cell sorting and single-cell RNA sequencing. This indicates a preleukemic origin of the IDH2 mutation within the context of clonal hematopoiesis. Transcriptomic and DNA methylation analyses revealed a distinct gene expression profile and a DNA hypermethylation phenotype in IDH2mt LenB-ALL, including IDH2mt-specific as well as lenalidomide-associated features. We propose that lenalidomide promotes the expansion of IDH2-mutated clonal hematopoiesis and, via IKAROS downregulation, induces a maturation arrest at the B-cell precursor stage. Subsequent genetic or epigenetic alterations render leukemogenesis independent of ongoing lenalidomide exposure. All these data define IDH2mt B-ALL as a distinct molecular subtype that is markedly overrepresented after lenalidomide treatment and highlight clonal hematopoiesis as a key contributing factor in the development of LenB-ALL.
Source: Blood
Authors: Johanna M. Horns, Thomas Beder, Axel Künstner, Malwine J. Barz, Sonja Bendig, Cecilia Bozzetti, Guranda Chitadze, Nikos Darzentas, Katharina Iben, Michaela Kotrova, José I. Martín-Subero, Mayukh Mondal, Martin Neumann, Raúl F. Pérez, Aeint-Steffen Ströh, Wiebke Weßels, Lennart Lenk, Lars Velten, Boris Böll, Krischan Braitsch, Veit Bücklein, Johannes Duell, Christoph Faul, Walter Fiedler, Maher Hanoun, Snjezana Janjetovic, Felix Klingler, Stefan Knop, Christoph Röllig, Stefan Schwartz, Bernd Spriewald, Björn Steffen, Klaus Wethmar, Hauke Busch, Nicola Gökbuget, Claudia D. Baldus, Lorenz Bastian, Monika Brüggemann
Institutions: University Hospital Schleswig-Holstein, University of Lübeck, Institució Catalana de Recerca i Estudis Avançats, Centro de Investigación Biomédica en Red de Cáncer, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Christian-Albrechts-Universität zu Kiel, Universidad Complutense de Madrid, Universitat Pompeu Fabra, Barcelona Institute of Science and Technology, Centre for Genomic Regulation, University Hospital Cologne, TUM Klinikum, Technical University of Munich, LMU Klinikum, Ludwig-Maximilians-Universität München, University of Würzburg, Universitätsklinikum Würzburg, Universitätsklinikum Tübingen, University of Tübingen, University Medical Center Hamburg-Eppendorf, Essen University Hospital, Helios Hospital Berlin-Buch, Nuremberg Hospital, Technische Universität Dresden, Humboldt-Universität zu Berlin, Charité - Universitätsmedizin Berlin, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Goethe University Frankfurt, University Hospital Frankfurt, University Hospital Münster
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,500
OpenAlex ID: W7135230780