Scientists uncover new vulnerability in acute myeloid leukemia

HOUSTON—Researchers at Baylor College of Medicine and collaborating institutions have identified a previously unrecognized weakness in acute myeloid leukemia (AML), suggesting that drugs designed to inhibit mutant FLT3 proteins may destroy leukemia cells through a second, highly destructive process. The study, published in Nature Cell Biology on Aug. 7, 2026, links FLT3-targeted treatment to ferroptosis, a form of cell death driven by the uncontrolled oxidation of cellular lipids. The finding could help explain why some AML cells respond to FLT3 inhibitors and may point toward strategies for overcoming treatment resistance while limiting damage to healthy tissue.

AML is an aggressive blood cancer in which abnormal myeloid cells accumulate in the bone marrow and interfere with the production of normal blood cells. Mutations in the gene encoding FLT3, a receptor tyrosine kinase that transmits growth and survival signals, are among the most common genetic alterations found in AML. These mutations can cause FLT3 to remain abnormally active, encouraging leukemia cells to multiply rapidly and resist normal controls on growth. Several drugs, including gilteritinib, have been developed to block mutant FLT3, but patients frequently experience treatment resistance or relapse.

“FLT3 mutations are one of the most common genetic drivers of AML,” said corresponding author Dr. Daisuke Nakada, Henry and Emma Meyer Professor in Molecular and Human Genetics at Baylor College of Medicine. Earlier work had established that FLT3 inhibition can stop leukemia cells from dividing and activate apoptosis, a programmed self-destruction pathway. Nakada and his colleagues investigated whether the drugs might also kill AML cells through a mechanism that does not depend solely on apoptosis. Their experiments revealed that the answer is ferroptosis, a distinct process that is increasingly recognized as an important vulnerability in cancer.

Ferroptosis occurs when cells lose the ability to control lipid peroxidation. In this process, reactive oxygen molecules attack polyunsaturated fatty acids within cellular membranes, generating unstable lipid compounds that damage membrane structure and disrupt essential cellular functions. Unlike apoptosis, which involves an organized dismantling of the cell, ferroptosis is associated with catastrophic oxidative injury. The researchers observed evidence of this process in mouse models, laboratory leukemia cell lines and patient-derived AML samples transplanted into animals, demonstrating that the mechanism was not restricted to a single experimental system.

The team traced the vulnerability to GPX4, an enzyme that protects cell membranes from lipid peroxidation. GPX4 is a selenoprotein, meaning that it contains the trace element selenium as part of its active structure. By reducing harmful lipid peroxides, GPX4 acts as one of the cell’s most important defenses against ferroptosis. The researchers found that mutant FLT3 supports the production of GPX4 and other selenoproteins in AML cells. When FLT3 is blocked, this production is disrupted, leaving leukemia cells increasingly exposed to oxidative damage.

According to the study, the effect is not simply a matter of FLT3 inhibitors switching off a growth signal. The drugs also appear to interfere with the cellular machinery required to make selenoproteins. As GPX4 levels fall, AML cells become less capable of neutralizing lipid peroxides. The resulting accumulation of oxidized lipids pushes the cells beyond a critical threshold, triggering ferroptotic death. This connection between mutant FLT3 signaling, selenium-dependent protein production and ferroptosis provides a biochemical explanation for why FLT3-mutant leukemia may be particularly sensitive to the treatment.

Analysis of samples from AML patients offered additional clues about resistance. Leukemia samples that had become resistant to gilteritinib frequently showed increased activity in genes involved in selenoprotein production. The pattern suggests that resistant cells may survive by strengthening the very protective pathway that FLT3 inhibitors weaken. By increasing their capacity to synthesize GPX4 and related proteins, the cells could restore their ability to control lipid peroxidation even while FLT3 signaling remains suppressed. This observation raises the possibility that the selenoprotein pathway could serve as a biomarker of resistance or a target for combination therapies.

The researchers also identified a potential influence outside the cancer cell itself: dietary vitamin E. Vitamin E is an antioxidant that can limit lipid oxidation, and experiments showed that dietary supplementation markedly reduced the effectiveness of gilteritinib in animal models. The result does not establish that ordinary dietary intake compromises treatment, nor does it provide a basis for patients to change supplements without medical advice. It does, however, highlight the importance of understanding how antioxidants may affect therapies that depend on oxidative damage to eliminate cancer cells. High-dose vitamin E supplementation could theoretically suppress the ferroptotic mechanism activated by FLT3 inhibition.

The findings position ferroptosis as a possible therapeutic lever in FLT3-mutant AML and suggest several avenues for future research. Drugs that further weaken GPX4 activity, disrupt selenium metabolism or increase lipid peroxidation might enhance the effects of FLT3 inhibitors, particularly in resistant disease. At the same time, any such approach would require careful dosing because ferroptosis-related processes also occur in normal tissues. The study was conducted by scientists from Baylor College of Medicine, the University of Texas MD Anderson Cancer Center, Texas A&M University and Washington University School of Medicine, with support from federal, philanthropic and Texas-based research programs. Further clinical studies will be needed to determine whether manipulating ferroptosis can improve outcomes for people with AML.

News Publication Date: Aug. 7, 2026.

Web References: Nature Cell Biology; https://doi.org/10.1038/s41556-026-02016-5

References: DOI: 10.1038/s41556-026-02016-5.