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A modified form of diphthamide causes immunotoxin resistance in a lymphoma cell line with a deletion of the WDR85 gene.

Abstract
HA22 is a recombinant immunotoxin that kills CD22-expressing cells by ADP-ribosylating and inactivating elongation factor-2 (EF2). HA22 is composed of an Fv that binds to CD22 fused to a portion of Pseudomonas exotoxin A. HA22 is very active in drug-resistant hairy cell leukemia but is less active in children with acute lymphoblastic leukemia. To understand why some patients do not respond to HA22, we isolated an HA22-resistant lymphoma cell line and showed that resistance was due to the inability of HA22 to ADP-ribosylate and inactivate EF2. We analyzed the diphthamide synthesis genes and found that the WDR85 gene was deleted. We show that WDR85 knockdown conferred HA22 resistance to sensitive cells and that sensitivity was restored by introduction of a WDR85 cDNA into resistant cells. Analysis of EF2 in the mutant cells revealed a novel form of diphthamide with an additional methyl group that prevented ADP-ribosylation and inactivation of EF2. The abnormal methylation appeared to be catalyzed by DPH5. Inactivation of the WDR85 gene could be a mechanism of immunotoxin resistance in patients undergoing immunotoxin therapy.
AuthorsHui Wei, Tapan K Bera, Alan S Wayne, Laiman Xiang, Simona Colantonio, Oleg Chertov, Ira Pastan
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 17 Pg. 12305-12 (Apr 26 2013) ISSN: 1083-351X [Electronic] United States
PMID23486472 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
Chemical References
  • Immunotoxins
  • Neoplasm Proteins
  • Peptide Elongation Factor 2
  • Proteins
  • Histidine
  • diphthamide
  • DPH7 protein, human
  • Methyltransferases
  • Carboxylic Ester Hydrolases
Topics
  • Carboxylic Ester Hydrolases
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Gene Deletion
  • Histidine (analogs & derivatives, genetics, metabolism)
  • Humans
  • Immunotoxins (pharmacology)
  • Lymphoma (drug therapy, genetics, metabolism)
  • Methylation (drug effects)
  • Methyltransferases (genetics, metabolism)
  • Neoplasm Proteins (genetics, metabolism)
  • Peptide Elongation Factor 2 (genetics, metabolism)
  • Proteins

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