A study published on July 7, 2026, in the journal Leukemia identified TET2 and TXNRD1 as key factors in resistance to the drug tagraxofusp in blastic plasmacytoid dendritic cell neoplasm (BPDCN). Researchers at The University of Texas MD Anderson Cancer Center co-led the study, which examined this resistance.

Tagraxofusp is the first Food and Drug Administration-approved treatment for BPDCN, an aggressive type of acute leukemia that usually arises from a rare immune cell found in bone marrow. Approximately 10 to 25% of newly diagnosed BPDCN patients may not initially respond to tagraxofusp treatment.

The study linked resistance to tagraxofusp with severe mutations in the TET2 gene and consistently lower levels of the TXNRD1 enzyme. Patients with normal or mild TET2 mutations responded better to treatment than those with severe TET2 mutations. The TXNRD1 enzyme is necessary to activate tagraxofusp's toxic component, which targets CD123, a surface marker overexpressed in BPDCN cells, by using the IL-3 marker.

Hannah Beird, Ph.D., a senior research scientist in Genomic Medicine, co-led the study. She stated, "Our findings show that specific cancer cells can effectively escape destruction by dialing down key enzymes that tagraxofusp needs in order to work." Beird added, "Armed with this information, we can begin to predict which patients are less likely to respond, and we can design smarter, more personalized treatments to help improve outcomes."

The researchers used single-cell sequencing of nearly 100,000 cells for their analysis. Most tumor cell types were eliminated by treatment except for a resistant group known as 'cluster 22.' Surviving cells in cluster 22 consistently showed lower expression levels of TXNRD1, and blocking TXNRD1 in preclinical models increased treatment resistance.

Combining tagraxofusp with the hypomethylating agent azacitidine restored key pathways and improved outcomes in preclinical models. Naveen Pemmaraju, M.D., professor of Leukemia and study co-leader, said, "This study highlights the importance of investigating rare and ultra-rare tumors for insights and breakthroughs that may potentially apply to other, even more common tumor types." He added, "Molecular investigations in rare blood cancers, such as this, may serve as a blueprint for novel techniques and approaches for other cancers with similar resistance phenomena." Tagraxofusp releases a toxin that shuts down protein production to destroy the cell after binding.

Why It Matters

This study identifies genetic and enzymatic factors associated with resistance to tagraxofusp, the only FDA-approved treatment for BPDCN. Understanding these resistance mechanisms could lead to more effective treatment strategies, particularly for the subset of BPDCN patients who do not respond to initial therapy. The findings also suggest that combining tagraxofusp with agents like azacitidine could overcome resistance, offering a potential path for improved patient outcomes in an aggressive form of leukemia.