Journal Article Review Ahead of print
PubMed: 42420551 DOI: 10.1007/s12672-026-05549-1
Leukemic architecture as a framework for risk stratification in NPM1-mutated acute myeloid leukemia.
Discov Oncol
Authors: Francesco Tarantini, Luisa Anelli, Antonella Zagaria, Cosimo Cumbo, Nicoletta Coccaro, Angela Minervini, Giuseppina Tota, Maria Rosa Conserva, Immacolata Redavid, Crescenzio Francesco Minervini, Elisa Parciante, Giorgina Specchia, Pellegrino Musto, Francesco Albano
Affiliations
- Hematology and Stem Cell Transplantation Unit, Azienda Ospedaliero Universitaria Consorziale Policlinico, Bari, 70124, Italy.
- Hematology and Stem Cell Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari "Aldo Moro", P.zza G. Cesare, 11, Bari, 70124, Italy.
- School of Medicine, University of Bari "Aldo Moro", Bari, 70124, Italy.
- Hematology and Stem Cell Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari "Aldo Moro", P.zza G. Cesare, 11, Bari, 70124, Italy.
Abstract
NPM1-mutated (NPM1c) acute myeloid leukemia (AML) has traditionally been considered a genetically defined entity associated with a favorable prognosis. However, growing evidence indicates that NPM1c AML comprises biologically and clinically heterogeneous disease states, in which NPM1c acts less as an autonomous prognostic determinant and more as a context-dependent organizer of leukemic architecture. Integrative transcriptomic and epigenomic studies have identified reproducible stemness-linked programs, including primitive and committed subtypes, the primitive phenotype being associated with inferior survival and increased relapse risk even within conventionally favorable groups. Single-cell and clonal architecture analyses further support a hierarchical model whereby early epigenetic lesions shape differentiation trajectories and constrain the phenotypic output of subsequent NPM1 and signaling mutations. In parallel, large-scale sequencing studies reveal non-random co-mutational patterns and variant allele frequency hierarchies, where epigenetic mutations frequently precede NPM1c and signaling alterations emerge later during leukemic evolution. Collectively, these findings support risk-stratification frameworks that integrate the leukemic cell state, transcriptional identity, and mutational hierarchy, moving from mutation-centric toward architecture-informed models for prognosis and therapeutic decision-making in NPM1c AML.
MeSH
Cells, Leukemia, Leukemia, Myeloid, Acute, Leukemia, Myeloid, Mutation, Prognosis