Decoding Leukemic Stem Cells in AML: From Identification to Targeted Eradication

Acute myeloid leukemia (AML) continues to pose significant therapeutic challenges, with high relapse rates driven largely by leukemic stem cells (LSCs), a rare, therapy-resistant population with self-renewal capacity, niche adaptation, and the ability to re-initiate disease. In this state-of-the-art review, we synthesize recent advances in LSC biology, addressing (i) how LSCs differ functionally and phenotypically from normal hemato-poietic stem cells, (ii) practical approaches for LSC quantification using multiparameter flow cytometry and LSC-enriched marker panels, (iii) the metabolic and epigenetic programs that enable LSC persistence under chemotherapy and contribute to measurable residual disease, and (iv) current therapeutic strategies targeting LSC eradication, in-cluding antibody-based therapies, apoptosis and metabolic inhibitors, and emerging epigenetic agents. We also examine the key translational barriers, particularly antigen overlap with normal progenitors, microenvironmental protection, and the need for assay harmonization, and propose a practical framework for integrating LSC assessment into risk stratification and therapeutic development.