IDH2 Clonal Hematopoiesis and IKAROS Loss Cooperate in a B-ALL Subtype after Lenalidomide Therapy for Multiple Myeloma - PubMed
7 hours ago
- #B-ALL
- #Lenalidomide
- #Clonal Hematopoiesis
- Lenalidomide, used in multiple myeloma therapy, increases the risk of secondary B-cell precursor acute lymphoblastic leukemia (B-ALL).
- 57 patients with lenalidomide-associated B-ALL (LenB-ALL) were studied, revealing three mutational subgroups: TP53mt (30%), IDH2mt (23%), and others including NRAS/KRASmt.
- IDH2 R140Q mutations were significantly more common in LenB-ALL compared to primary B-ALL.
- IKZF1 intragenic deletions, often subclonal and RAG-mediated, were found in 54% of IDH2mt LenB-ALL cases.
- IDH2 mutations persisted during remission and were found in both lymphoid and myeloid cells, indicating a preleukemic origin.
- Transcriptomic and DNA methylation analyses showed distinct gene expression and hypermethylation in IDH2mt LenB-ALL.
- Lenalidomide promotes expansion of IDH2-mutated clonal hematopoiesis and induces B-cell precursor maturation arrest via IKAROS downregulation.
- Subsequent genetic or epigenetic changes lead to leukemogenesis independent of ongoing lenalidomide exposure.
- IDH2mt B-ALL is a distinct molecular subtype overrepresented after lenalidomide treatment, with clonal hematopoiesis as a key factor.