Acute myeloid leukemia-targeted toxin activates both apoptotic and necroptotic death mechanisms

Henrick Horita, Arthur E. Frankel, Andrew Thorburn

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Background: Acute myelogenous leukemia (AML) is the second most common leukemia with approximately 13,410 new cases and 8,990 deaths annually in the United States. A novel fusion toxin treatment, diphtheria toxin GM-CSF (DT-GMCSF) has been shown to selectively eliminate leukemic repopulating cells that are critical for the formation of AML. We previously showed that DT-GMCSF treatment of U937 cells, an AML cell line, causes activation of caspases and the induction of apoptosis. Methods and Findings: In this study we further investigate the mechanisms of cell death induced by DT-GMCSF and show that, in addition to the activation of caspase-dependent apoptosis, DT-GMCSF also kills AML cells by simultaneously activating caspase-independent necroptosis. These mechanisms depend on the ability of the targeted toxin to inhibit protein synthesis, and are not affected by the receptor that is targeted or the mechanism through which protein synthesis is blocked. Conclusions: We conclude that fusion toxin proteins may be effective for treating AML cells whether or not they are defective in apoptosis.

Original languageEnglish (US)
Article numbere3909
JournalPLoS One
Volume3
Issue number12
DOIs
StatePublished - Dec 11 2008

Fingerprint

Diphtheria Toxin
Immunotoxins
myeloid leukemia
Acute Myeloid Leukemia
leukemia
toxins
Granulocyte-Macrophage Colony-Stimulating Factor
Caspases
death
Apoptosis
caspases
Fusion reactions
Chemical activation
apoptosis
Proteins
Cell death
U937 Cells
protein synthesis
cells
Cells

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Acute myeloid leukemia-targeted toxin activates both apoptotic and necroptotic death mechanisms. / Horita, Henrick; Frankel, Arthur E.; Thorburn, Andrew.

In: PLoS One, Vol. 3, No. 12, e3909, 11.12.2008.

Research output: Contribution to journalArticle

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