Abstract
Moxetumomab pasudotox (HA22) is an immunotoxin with an anti-CD22 Fv fused to a portion of Pseudomonas exotoxin A that kills CD22 expressing ALL cells. HA22 produced significant responses in some cases of ALL. To understand how to increase response rate, we isolated HA22-resistant KOPN-8 cells and found that HA22 cannot inactivate elongation factor-2 (EF2) due to low levels of DPH1 RNA and protein. Resistance was associated with methylation of the CpG island in the DPH1 promoter. 5-Azacytidine prevented resistance and methylation of the CpG residues and merits evaluation to determine if it can increase the efficacy of HA22 in ALL.
Keywords:
ADP-ribosylation; DNA methylation; Diphthamide synthesis; Drug resistance; Epigenetic regulation.
Published by Elsevier Ltd.
Publication types
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antimetabolites, Antineoplastic / pharmacology
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Apoptosis / drug effects*
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Azacitidine / pharmacology
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Bacterial Toxins / pharmacology*
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Blotting, Western
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Cell Proliferation / drug effects
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DNA Methylation / drug effects*
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Exotoxins / pharmacology*
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Gene Silencing
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Humans
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Minor Histocompatibility Antigens
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Promoter Regions, Genetic / genetics*
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Tumor Cells, Cultured
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Tumor Suppressor Proteins / antagonists & inhibitors
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Tumor Suppressor Proteins / genetics*
Substances
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Antimetabolites, Antineoplastic
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Bacterial Toxins
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DPH1 protein, human
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Exotoxins
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Minor Histocompatibility Antigens
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RNA, Messenger
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Tumor Suppressor Proteins
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immunotoxin HA22
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Azacitidine