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

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

Authors:	Sirenko, M.; Lee, S.; Sun, Z.; Chaligne, R.; Loghavi, S.; Asimomitis, G.; Brierley, C. K.; Bernard, E.; Cai, S. F.; Myers, R. M.; Nadorp, B.; Sango, J.; Lallo, M.; Levine, M. F.; Domenico, D.; Arango Ossa, J. E.; Medina-Martinez, J. S.; Menghrajani, K.; Lasry, A.; Mims, A. S.; Desai, H.; Laganson, A.; Famulare, C.; Patel, M.; Lozanski, G.; Bolton, K. L.; Viny, A. D.; Roshal, M.; Levine, R. L.; Papapetrou, E. P.; Stein, E. M.; Landau, D. A.; Eisfeld, A. K.; Aifantis, I.; Papaemmanuil, E.
Article Title:	Deconvoluting clonal and cellular architecture in IDH-mutant acute myeloid leukemia
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. © 2025
Keywords:	relapse; targeted therapy; treatment resistance; acute myeloid leukemia; clonal evolution; single-cell transcriptomics; clonal architecture; idh1/2 mutations; cellular hierarchy; idh inhibitors
Journal Title:	Cell Stem Cell
Volume:	32
Issue:	7
ISSN:	1934-5909
Publisher:	Cell Press
Publication status:	Published
Date Published:	2025-07-03
Online Publication Date:	2025-05-22
Start Page:	1102
End Page:	1121.e5
Language:	English
DOI:	10.1016/j.stem.2025.04.012
PUBMED:	40409258
PROVIDER:	scopus
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-105006514037&doi=10.1016%2fj.stem.2025.04.012&partnerID=40&md5=6a681f49a231bb1aacb988f135f996e2
Notes:	Article -- MSK corresponding author is Elli Papaemmanuil -- Source: Scopus