ArticleThe Journal of biological chemistry2013
A modified form of diphthamide causes immunotoxin resistance in a lymphoma cell line with a deletion of the WDR85 gene.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 30 citations in OpenAlex.
- Synthesis of an Anti-CD7 Recombinant Immunotoxin Based on PE24 in CHO andInternational journal of molecular sciences · 2022Article
- Reduced cytotoxicity by mutation of lysine 590 ofImmunotherapy advances · 2022Article
- Diphthamide-deficiency syndrome: a novel human developmental disorder and ribosomopathy.European journal of human genetics : EJHG · 2020Article
- Mechanisms of Resistance to Immunotoxins ContainingBiomolecules · 2020Review
- Diphthamide affects selenoprotein expression: Diphthamide deficiency reduces selenocysteine incorporation, decreases selenite sensitivity and pre-disposes to oxidative stress.Redox biology · 2019Article
- 5-Azacytidine prevents relapse and produces long-term complete remissions in leukemia xenografts treated with Moxetumomab pasudotox.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Importance of diphthamide modified EF2 for translational accuracy and competitive cell growth in yeast.PloS one · 2018Article
- Influence of DPH1 and DPH5 Protein Variants on the Synthesis of Diphthamide, the Target of ADPRibosylating Toxins.Toxins · 2017Article
- Wide Variability in the Time Required for Immunotoxins to Kill B Lineage Acute Lymphoblastic Leukemia Cells: Implications for Trial Design.Clinical cancer research : an official journal of the American Association for Cancer Research · 2016Article
- Novel angiogenin mutants with increased cytotoxicity enhance the depletion of pro-inflammatory macrophages and leukemia cells ex vivo.Cancer immunology, immunotherapy : CII · 2015Article
- Loss of diphthamide pre-activates NF-κB and death receptor pathways and renders MCF7 cells hypersensitive to tumor necrosis factor.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Whole-genome RNAi screen highlights components of the endoplasmic reticulum/Golgi as a source of resistance to immunotoxin-mediated cytotoxicity.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Article
- Dph7 catalyzes a previously unknown demethylation step in diphthamide biosynthesis.Journal of the American Chemical Society · 2014Article
- Immunotoxins for leukemia.Blood · 2014Review
- The biosynthesis and biological function of diphthamide.Critical reviews in biochemistry and molecular biologyReview
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Authors and funding
7 authors at 5 institutions in 2 countries.
Funding
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.
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