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Hitting the bullseye with a nonlethal payload: resistance in CD123-positive malignancies
Lukasz P. Gondek
Lukasz P. Gondek
Published October 14, 2019
Citation Information: J Clin Invest. 2019;129(11):4590-4592. https://doi.org/10.1172/JCI132443.
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Commentary

Hitting the bullseye with a nonlethal payload: resistance in CD123-positive malignancies

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Abstract

The interleukin 3 receptor (CD123) is a transmembrane protein that is absent or hardly expressed on normal hematopoietic stem cells, but highly expressed on the surface of cancer cells in several hematologic malignancies. In this issue of the JCI, Togami et al. investigated the mechanism of resistance to the recently approved anti-CD123 agent tagraxofusp, which consists of interleukin 3 fused to a truncated diphtheria toxin (DT) molecule. The authors demonstrated that loss of the intracellular target for DT, diphthamide, a conservative modification of histidine 715 in eukaryotic elongation factor 2, resulted in tagraxofusp resistance. Specifically, hypermethylation of the DPH1 gene, encoding a key enzyme in diphthamide synthesis, resulted in diphthamide loss. Notably, treatment with a DNA hypomethylating agent restored DPH1 expression and resensitized cells to tagraxofusp. The recognition of this resistance mechanism may have important clinical implications and lead to the development of more effective multiagent therapies.

Authors

Lukasz P. Gondek

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Figure 1

Mechanism of action and resistance to tagraxofusp.

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Mechanism of action and resistance to tagraxofusp.
(A) Tagraxofusp-media...
(A) Tagraxofusp-mediated cell killing includes IL-3R engagement, endocytosis, acidification, and translocation of DT into the cytoplasm; ADP-ribosylation of diphthamide on eEF2, and inhibition of protein synthesis. (B) Model showing that hypermethylation of the DPH1 promoter prevents diphthamide modification of eEF2 and confers tagraxofusp resistance, while demethylation of the DPH1 promoter restores diphthamide synthesis and sensitivity. T, translocation domain; C, catalytic domain.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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