In this issue of Haematologica, a study by Colom Díaz et al.1 propels Metallothionein 1 (MT1) into the spotlight as a newly identified mediator of malignant cell growth in a model of Dnmt3a;Npm1-mutant acute myeloid leukemia (AML) and in human disease. AML remains a deadly malignancy despite significant advances in diagnosis, therapy, and supportive care, with a 5-year survival rate for adults in the United States of about 33%.2 While presence of NPM1 mutations is generally associated with favorable outcomes, co-occurring mutations in DNMT3A confer a more grim prognosis due to increased risk of relapse,3,4 emphasizing the urgent need for new mechanism-driven targeted strategies in this patient population.
Mt1 is a low molecular weight, cysteine-rich intracellular protein that is widely expressed across most organs. It plays a crucial role in maintaining cellular metal ion homeostasis, including regulating metal balance, alleviating heavy metal toxicity, and defending against oxidative stress, inflammation, and other environmental insults and stressors.5,6 This study adds a new role to its list of responsibilities - safeguarding AML cells from ferroptotic death.
Figure 1.Mt1 is a dependency in mouse and human Dnmt3a;Npm1-mutant acute myeloid leukemia. This schematic illustrates the differential expression and functional impact of metallothionein isoforms in mouse and human acute myeloid leukemia (AML) harboring DNMT3A and NPM1 mutations. In mouse AML cells (left), co-occurrence of Dnmt3aR878H/+ and Npm1cA/+ leads to increased expression of Mt1, and its knockout results in decreased cell growth. In human AML cells (right), co-mutated DNMT3AR882C/+ and NPM1CA/+ drive upregulation of MT1G expression, and knockout of MT1G similarly reduces cell growth.
This study identifies Mt1 as one of the top genes uniquely expressed in Dnmt3a;Npm1-mutant AML progenitors compared with other molecular disease subtypes and normal bone marrow counterparts. Mt1 expression is critical for the survival of leukemia cells: thus, disrupting Mt1 in Dnmt3a;Npm1-mutant AML by CRISPR-Cas9-sgRNA complexes (RNP) decreased cell proliferation in vitro and delayed disease progression in animal models. Interestingly, elevated Mt1 was highly specific to Dnmt3a;Npm1-mutant AML as it was not observed in cells with Dnmt3a or Npm1 single-gene alterations alone, indicating cooperativity of both mutations as a critical mechanism to achieve transcriptional upregulation of Mt1.
Unlike a single Mt1 gene in mice, humans feature eight functional MT1 paralogs: MT1A, MT1B, MT1E, MT1F, MT1G, MT1H, MT1M, and MT1X.7 Among these, only MT1F, MT1G, MT1H and MT1X show increased expression in human AML compared to normal bone marrow samples.1 In the human OCI-AML3 cell line, a well-established model of DNMT3A;NPM1-mutant AML, MT1G is highly expressed compared to normal bone marrow cells. Furthermore, disruption of MT1G decreases viability exclusively in DNMT3A;NPM1-mutant AML cells, but not in OCI-AML2 cells with DNMT3A mutation alone.
These findings firm up MT1G as a specific dependency in AML with DNMT3A and NPM1 co-mutation, that is not observed with DNMT3A mutation alone (Figure 1).
In conclusion, the study by Colom Díaz et al. identifies MT1 as a novel vulnerability in Dnmt3a;Npm1-mutant AML, highlighting a previously underappreciated role of metal metabolism in the pathophysiology of leukemia. Their findings suggest that targeting MT1 may selectively impair malignant cells while sparing normal hematopoiesis, offering a promising pathway for future precision therapies. However, limitations remain. The exact mechanism whereby DNMT3A and NPM1 mutations cooperate to regulate Mt1 expression requires further investigation. Additionally, no pharmacological inhibitors for Mt1 or MT1G are currently available. This study represents a timely call for the research community and industry partners to transform this newly identified metabolic mechanism co-opted by leukemia into a targetable vulnerability. The challenge ahead is to rapidly advance these discoveries toward clinical translation, for the benefit of AML patients.
Footnotes
- Received August 27, 2025
- Accepted September 9, 2025
Correspondence
Disclosures
No conflicts of interest to disclose.
Contributions
BY and OAG wrote the manuscript.
References
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