Diphtheria toxin fused to human interleukin-3 is toxic to blasts from patients with myeloid leukemias

A. E. Frankel, J. A. McCubrey, M. S. Miller, S. Delatte, J. Ramage, M. Kiser, G. L. Kucera, R. L. Alexander, M. Beran, E. P. Tagge, R. J. Kreitman, D. E. Hogge

Research output: Contribution to journalArticlepeer-review

96 Scopus citations

Abstract

Leukemic blasts from patients with acute phase chronic myeloid leukemic and refractory acute myeloid leukemia are highly resistant to a number of cytotoxic drugs. To overcome multi-drug resistance, we engineered a diphtheria fusion protein by fusing human interleukin-3 (IL3) to a truncated form of diphtheria toxin (DT) with a (G4S)2 linker (L), expressed and purified the recombinant protein, and tested the cytotoxicity of the DTLIL3 molecule on human leukemias and normal progenitors. The DTLIL3 construct was more cytotoxic to interleukin-3 receptor (IL3R) bearing human myeloid leukemia cell lines than receptor-negative cell lines based on assays of cytotoxicity using thymidine incorporation, growth in semi-solid medium and induction of apoptosis. Exposure of mononuclear cells to 680 pM DTLIL3 for 48 h in culture reduced the number of cells capable of forming colonies in semi-solid medium (colony-forming units leukemia) ≥ 10-fold in 4/11 (36%) patients with myeloid acute phase chronic myeloid leukemia (CML) and 3/9 (33%) patients with acute myeloid leukemia (AML). Normal myeloid progenitors (colony-forming unit granulocyte-macrophage) from five different donors treated and assayed under identical conditions showed intermediate sensitivity with three- to five-fold reductions in colonies. The sensitivity to DTLIL3 of leukemic progenitors from a number of acute phase CML patients suggests that this agent could have therapeutic potential for some patients with this disease.

Original languageEnglish (US)
Pages (from-to)576-585
Number of pages10
JournalLeukemia
Volume14
Issue number4
DOIs
StatePublished - 2000

Keywords

  • Acute myeloid leukemia
  • Chronic myeloid leukemia
  • Diphtheria fusion toxin
  • Interleukin-3

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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