<i>IDH2</i> clonal hematopoiesis and IKAROS loss cooperate in a B-ALL subtype after lenalidomide therapy for multiple myeloma
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&lt; .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.
Article Details
Authors (38)
Johanna M. Horns
1Department of Internal Medicine II (Hematology/Oncology), University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
Thomas Beder
Axel Künstner
Malwine J. Barz
Sonja Bendig
1Department of Internal Medicine II (Hematology/Oncology), University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
Cecilia Bozzetti
1Department of Internal Medicine II (Hematology/Oncology), University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
Guranda Chitadze
1Department of Internal Medicine II (Hematology/Oncology), University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
Nikos Darzentas
1Department of Internal Medicine II (Hematology/Oncology), University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
Katharina Iben
1Department of Internal Medicine II (Hematology/Oncology), University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
Michaela Kotrova
1Department of Internal Medicine II (Hematology/Oncology), University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
José I. Martin-Subero
Mayukh Mondal
Martin Neumann
Raúl F. Pérez
Aeint-Steffen Ströh
1Department of Internal Medicine II (Hematology/Oncology), University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
Wiebke Wessels
Lennart Lenk
10Department of Pediatrics I, University Hospital Schleswig-Holstein, Kiel, Germany
Lars Velten
Boris Böll
13Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
Krischan Braitsch
14Department of Medicine III, TUM University Hospital, Technical University of Munich, Munich, Germany
Veit Bücklein
Ludwig Maximilian University Hospital, Munich, Germany
Johannes Duell
16Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany
Christoph Faul
17Department of Internal Medicine II, Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany
Walter Fiedler
Maher Hanoun
19Department of Hematology and Stem Cell Transplantation, University Hospital Essen, Essen, Germany
Snjezana Janjetovic
20Department of Hematology and Cell Therapy, Helios Klinikum Berlin-Buch, Berlin, Germany
Felix Klingler
18Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Stefan Knop
16Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany
Christoph Röllig
22Department of Internal Medicine I, University Hospital TU Dresden, Dresden, Germany
Stefan Schwartz
23Department of Hematology, Oncology and Cancer Immunology (Campus Benjamin Franklin), Charité– Universitätsmedizin Berlin, corporate member of Freie Universität and Humboldt-Universität zu Berlin, Berlin, Germany
Bernd Spriewald
25Department of Internal Medicine 5 - Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Uniklinik Erlangen, Erlangen, Germany
Björn Steffen
26Department of Medicine II, Hematology/Oncology, Goethe University Frankfurt, University Hospital, Frankfurt, Germany
Klaus Wethmar
27Department of Medicine A, Hematology, Oncology, Hemostaseology and Pneumology, University Hospital Münster, Münster, Germany
Hauke Busch
Nicola Gökbuget
26Department of Medicine II, Hematology/Oncology, Goethe University Frankfurt, University Hospital, Frankfurt, Germany
Claudia D. Baldus
Lorenz Bastian
Monika Brüggemann
1Department of Internal Medicine II (Hematology/Oncology), University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany