Metallothionein Isoforms in Acute Myeloid Leukemia: Roles in Survival, Differentiation, and Stress Adaptation

Metallothioneins (MTs) are cysteine-rich metal-binding proteins traditionally recognized for their roles in metal homeostasis and antioxidant defense. Recent studies have revealed broader and functionally diverse roles of MT isoforms in acute myeloid leukemia (AML). This review summarizes current evidence regarding MT-mediated regulation of leukemic cell survival, differentiation, and therapy-associated stress adaptation. MT1 family members, particularly MT1X and MT1G, have been associated with proliferation, chemoresistance, and differentiation blockade in specific experimental contexts, whereas MT2A and MT3 exhibit tumor-suppressive effects in selected AML models. MT isoforms also participate in oxidative stress adaptation and redox regulation, including responses to azacitidine, doxorubicin, and ferroptotic stress. However, the available evidence is derived largely from cell-line studies, selected molecular subtypes, transcriptomic analyses, and limited primary-patient datasets. Accordingly, isoform-specific MT functions should be interpreted as context-dependent rather than uniformly applicable across AML. Further validation in independent primary AML cohorts and genetically defined subtypes is required to establish their clinical utility as biomarkers or therapeutic targets.