Methylation of the DPH1 promoter causes immunotoxin resistance in acute lymphoblastic leukemia cell line KOPN-8.

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.

• Authors: Xiaobo Hu, Hui Wei, Laiman Xiang, Oleg Chertov, Alan S Wayne, Tapan K Bera, Ira Pastan
• Journal: Leukemia research (Leuk Res) Vol. 37 Issue 11 Pg. 1551-6 (Nov 2013) ISSN: 1873-5835 [Electronic] England
• PMID: 24070652 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Published by Elsevier Ltd.

Chemical References

• Antimetabolites, Antineoplastic
• Bacterial Toxins
• DPH1 protein, human
• Exotoxins
• Minor Histocompatibility Antigens
• RNA, Messenger
• Tumor Suppressor Proteins
• immunotoxin HA22
• Azacitidine

Topics

• Antimetabolites, Antineoplastic (pharmacology)
• Apoptosis (drug effects)
• Azacitidine (pharmacology)
• Bacterial Toxins (pharmacology)
• Blotting, Western
• Cell Proliferation (drug effects)
• DNA Methylation (drug effects)
• Exotoxins (pharmacology)
• Gene Silencing
• Humans
• Minor Histocompatibility Antigens
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics, pathology)
• Promoter Regions, Genetic (genetics)
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Cells, Cultured
• Tumor Suppressor Proteins (antagonists & inhibitors, genetics)