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

Leuk Res. 2013 Nov;37(11):1551-6. doi: 10.1016/j.leukres.2013.08.005. Epub 2013 Aug 13.

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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / 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
  • Tumor Suppressor Proteins / genetics*

Substances

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