Preclinical targeting of leukemia-initiating cells in the development future biologics for acute myeloid leukemia.

Introduction: Leukemia-initiating cells (LICs) are a critical subset of cells driving acute myeloid leukemia (AML) relapse and resistance to therapy. They possess unique properties, including metabolic, epigenetic, and microenvironmental dependencies, making them promising therapeutic targets.

Areas covered: This review summarizes preclinical advances in targeting AML LICs, including strategies to exploit metabolic vulnerabilities, such as the reliance on oxidative phosphorylation (OXPHOS), through the use of mitochondrial inhibitors; target epigenetic regulators like DOT1L (Disruptor of Telomeric Silencing 1-like) to disrupt LIC survival mechanisms; develop immunotherapies, including CAR (chimeric antigen receptor) T-cell therapy, and bispecific antibodies; and disrupt LIC interactions with the bone marrow microenvironment by inhibiting supportive niches.

Expert opinion: LIC-targeted therapies hold significant promise for revolutionizing AML treatment by reducing relapse rates and improving long-term outcomes. However, challenges such as LIC heterogeneity, therapy resistance, and associated toxicity persist. Recent studies have illuminated the distinct biological characteristics of LICs, advancing our understanding of their behavior and vulnerabilities. These insights offer new opportunities to target LICs at earlier disease stages and to explore combination therapies with other targeted treatments, ultimately enhancing therapeutic efficacy and improving patient outcomes.