ArticleThe Journal of clinical investigation2019
DNA methyltransferase inhibition overcomes diphthamide pathway deficiencies underlying CD123-targeted treatment resistance.
Article in The Journal of clinical investigation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
40 citing papers in PubMed, 85 citations in OpenAlex.
- Decreased TXNRD1 is associated with resistance to tagraxofusp in blastic plasmacytoid dendritic cell neoplasms, as seen in phase II.Leukemia · 2026Trial
- Pivekimab Sunirine in Blastic Plasmacytoid Dendritic Cell Neoplasm.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2026Trial
- Approval of tagraxofusp-erzs for blastic plasmacytoid dendritic cell neoplasm.Blood advances · 2020Trial
- Current and future therapies for acute myeloblastic leukemia.Journal of hematology & oncology · 2026Review
- Article
- Prospective clinical trials of venetoclax and hypomethylating agents for relapsed BPDCN.Blood neoplasia · 2025Article
- Immunotherapies Targeting CD123 and CD303: A New Frontier in Treating Blastic Plasmacytoid Dendritic Cell Neoplasm.International journal of molecular sciences · 2025Review
- Diagnostic approach to blastic plasmacytoid dendritic cell neoplasm: historical perspectives and current understanding.Journal of clinical and experimental hematopathology : JCEH · 2025Review
- Elongation factor 2 in cancer: a promising therapeutic target in protein translation.Cellular & molecular biology letters · 2024Review
- BPDCN: state of the art.Hematology. American Society of Hematology. Education Program · 2024Review
- Overcoming Tagraxofusp-Erzs Monotherapy Resistance in Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) in a Real-World Clinical Setting.Journal of immunotherapy and precision oncology · 2024Article
- Simultaneous blastic plasmacytoid dendritic cell neoplasm and myelofibrosis: A case report.Oncology letters · 2024Article
- Unmet Horizons: Assessing the Challenges in the Treatment ofJournal of clinical medicine · 2024Review
- Phase 1b trial of tagraxofusp in combination with azacitidine with or without venetoclax in acute myeloid leukemia.Blood advances · 2024Article
- Breakthrough in Blastic Plasmacytoid Dendritic Cell Neoplasm Cancer Therapy Owing to Precision Targeting of CD123.International journal of molecular sciences · 2024Review
- Venetoclax combined with azacitidine in blastic plasmacytoid dendritic cell neoplasm: a case report and comprehensive review on the current and future treatment.Frontiers in medicine · 2024Article
- Real-world evidence on tagraxofusp for blastic plasmacytoid dendritic cell neoplasm - collected cases from a single center and case reports.Frontiers in oncology · 2024Article
- Tagraxofusp for blastic plasmacytoid dendritic cell neoplasm: a 2-speed cure in the United States and European Union.Blood advances · 2023Article
- Review
- Expanding the Immunophenotypic Spectrum of Neoplastic and Reactive Plasmacytoid Dendritic Cells.American journal of clinical pathology · 2023Article
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Authors and funding
17 authors at 4 institutions in 1 country.
Funding
Abstract
The interleukin-3 receptor α subunit, CD123, is expressed in many hematologic malignancies including acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN). Tagraxofusp (SL-401) is a CD123-targeted therapy consisting of interleukin-3 fused to a truncated diphtheria toxin payload. Factors influencing response to tagraxofusp other than CD123 expression are largely unknown. We interrogated tagraxofusp resistance in patients and experimental models and found that it was not associated with CD123 loss. Rather, resistant AML and BPDCN cells frequently acquired deficiencies in the diphthamide synthesis pathway, impairing tagraxofusp's ability to ADP-ribosylate cellular targets. Expression of DPH1, encoding a diphthamide pathway enzyme, was reduced by DNA CpG methylation in resistant cells. Treatment with the DNA methyltransferase inhibitor azacitidine restored DPH1 expression and tagraxofusp sensitivity. We also developed a drug-dependent ADP-ribosylation assay in primary cells that correlated with tagraxofusp activity and may represent an additional novel biomarker. As predicted by these results and our observation that resistance also increased mitochondrial apoptotic priming, we found that the combination of tagraxofusp and azacitidine was effective in patient-derived xenografts treated in vivo. These data have important implications for clinical use of tagraxofusp and led to a phase 1 study combining tagraxofusp and azacitidine in myeloid malignancies.
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