IDH2 clonal hematopoiesis and IKAROS loss cooperate in a B-ALL subtype after lenalidomide therapy for multiple myeloma

Horns JM, Beder T, Künstner A, Barz MJ, Bendig S, Bozzetti C, Chitadze G, Darzentas N, Iben K, Kotrova M, Martín-Subero JI, Mondal M, Neumann M, Pérez RF, Ströh AS, Weßels W, Lenk L, Velten L, Böll B, Braitsch K, Bücklein V, Duell J, Faul C, Fiedler W, Hanoun M, Janjetovic S, Klingler F, Knop S, Röllig C, Schwartz S, Spriewald B, Steffen B, Wethmar K, Busch H, Gökbuget N, Baldus CD, Bastian L, Brüggemann M (2026)

Publication Type: Journal article

Publication year: 2026

Journal

DOI: 10.1182/blood.2025031047

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.

Authors with CRIS profile

Involved external institutions

Universitätsklinikum Schleswig-Holstein (UKSH) Germany (DE) Universität zu Lübeck Germany (DE) Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Spain (ES) Deutsche Forschungsgemeinschaft (DFG) Germany (DE) Centre for Genomic Regulation (CRG) Spain (ES) Universitätsklinikum Köln Germany (DE) Technische Universität München (TUM) Germany (DE) Klinikum der Universität München (LMU Klinikum) Germany (DE) Universitätsklinikum Würzburg Germany (DE) Universitätsklinikum Tübingen Germany (DE) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) Universitätsklinikum Essen Germany (DE) HELIOS Kliniken Germany (DE) Universitätsklinikum Carl Gustav Carus Dresden Germany (DE) Charité - Universitätsmedizin Berlin Germany (DE) Universitätsklinikum Frankfurt am Main (KGU) Germany (DE) Universitätsklinikum Münster Germany (DE)

How to cite

APA:

Horns, J.M., Beder, T., Künstner, A., Barz, M.J., Bendig, S., Bozzetti, C.,... Brüggemann, M. (2026). IDH2 clonal hematopoiesis and IKAROS loss cooperate in a B-ALL subtype after lenalidomide therapy for multiple myeloma. Blood. https://doi.org/10.1182/blood.2025031047

MLA:

Horns, Johanna M., et al. "IDH2 clonal hematopoiesis and IKAROS loss cooperate in a B-ALL subtype after lenalidomide therapy for multiple myeloma." Blood (2026).

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