Deconvoluting clonal and cellular architecture in IDH-mutant acute myeloid leukemia.

Publication Type	Academic Article
Authors	Sirenko M, Lee S, Sun Z, Chaligne R, Loghavi S, Asimomitis G, Brierley C, Bernard E, Cai S, Myers R, Nadorp B, Sango J, Lallo M, Levine M, Domenico D, Arango Ossa J, Medina-Martinez J, Menghrajani K, Lasry A, Mims A, Desai H, Laganson A, Famulare C, Patel M, Lozanski G, Bolton K, Viny A, Roshal M, Levine R, Papapetrou E, Stein E, Landau D, Eisfeld A, Aifantis I, Papaemmanuil E
Journal	Cell Stem Cell
Volume	32
Issue	7
Pagination	1102-1121.e5
Date Published	05/22/2025
ISSN	1875-9777
Keywords	Leukemia, Myeloid, Acute, Isocitrate Dehydrogenase, Mutation
Abstract	Isocitrate dehydrogenase 1/2 (IDH) mutations are early initiating events in acute myeloid leukemia (AML). The complex clonal architecture and cellular heterogeneity in IDH-mutant AML underlies the heterogeneous clinical presentation and outcomes. Integrating single-cell genotyping and transcriptomics, we demonstrate a stem-like and inflammatory phenotype of IDH-mutant AML and identify clone-specific programs associated with NPM1, NRAS, and SRSF2 co-mutations. Furthermore, these clones had distinct responses to treatment with combination IDH inhibitors and chemotherapy, including elimination, reconstitution of myeloid differentiation, or retention within progenitor populations. At relapse after IDH inhibitor monotherapy, we identify upregulated stemness, inflammation, mitochondrial metabolism, and anti-apoptotic factors, as well as downregulated major histocompatibility complex (MHC) class II antigen presentation. At the pre-leukemic stage, we observe upregulation of IDH2-associated pathways, including inflammation. We deliver a detailed phenotyping of IDH-mutant AML and a framework for dissecting contributions of recurrently mutated genes in AML at diagnosis and following therapy, with implications for precision medicine.
DOI	10.1016/j.stem.2025.04.012
PubMed ID	40409258
PubMed Central ID	PMC12857296