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

Research output: Contribution to journalReview article

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.

Original languageEnglish (US)
Pages (from-to)4590-4592
Number of pages3
JournalJournal of Clinical Investigation
Volume129
Issue number11
DOIs
StatePublished - Nov 1 2019

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Diphtheria Toxin
Interleukin-3 Receptors
Peptide Elongation Factor 2
Neoplasms
Interleukin-3
Hematologic Neoplasms
Hematopoietic Stem Cells
Histidine
DNA
Enzymes
Genes
diphthamide
Proteins
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

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Hitting the bullseye with a nonlethal payload : Resistance in CD123-positive malignancies. / Gondek, Lukasz P.

In: Journal of Clinical Investigation, Vol. 129, No. 11, 01.11.2019, p. 4590-4592.

Research output: Contribution to journalReview article

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