Methylation of the DPH1 promoter causes immunotoxin resistance in acute lymphoblastic leukemia cell line KOPN-8.
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.
Laboratory of Molecular Biology, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA.
Xiaobo
X
Hu
Hui
H
Wei
Laiman
L
Xiang
Oleg
O
Chertov
Alan S
AS
Wayne
Tapan K
TK
Bera
Ira
I
Pastan
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001374:Azacitidine / Q000494:pharmacology; D001427:Bacterial Toxins / Q000494:pharmacology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects*; D005098:Exotoxins / Q000494:pharmacology*; D020868:Gene Silencing; D006801:Humans; D015778:Minor Histocompatibility Antigens; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*
D000964:Antimetabolites, Antineoplastic; D001427:Bacterial Toxins; C121987:DPH1 protein, human; D005098:Exotoxins; D015778:Minor Histocompatibility Antigens; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; C541974:immunotoxin HA22; D001374:Azacitidine
ADP-ribosylation; DNA methylation; Diphthamide synthesis; Drug resistance; Epigenetic regulation