Diphtheria toxin fused to human gm-csf is toxic to primary malignant progenitors from patients with AML, JMML and CMML

A. Frankel, C. Eaves, P. Hall, R. Kreitman, M. Lilly, M. Heran, Bc

Research output: Contribution to journalArticle

Abstract

Human GM-CSF fused to a truncated diphtheria toxin (DT388GM-CSF) was expressed in E. coli, denatured, refolded, and purified by anion exchange and size exclusion chromatography. This fusion toxin was found to be toxic in vitro to GM-CSF receptor-bearing cell lines and primary leukemic clonogenic progenitors from patients with AML (27/28), JMML (5/7), and CMML (12/21), whereas, clonogenic progenitors in normal bone marrow samples (6/6) were insensitive to the protein under identical treatment conditions. Cell lines bearing mutant GM-CSF receptors (alpha term 1 plus beta) and cell lines with overexpression of anti-apoptotic proteins (Bcl-2 and Bcl-xl) were less sensitive to DT388-GM-CSF, and showed an increased IC50 of 2.5- to 25-fold. SCID mice inoculated IV with cells from a human leukemic cell line (HL60) and then treated on days 2 to 6 with 84 ug/kg/d of DT388-GM-CSF i.p. had a significantly (p < 0.001) prolonged survival (median survival = 83 days vs 45 days for the untreated animals) and 6 mice in the test group survived > 150 days. DT388-GM-CSF has thus been shown to display marked antileukemic efficacy in vitro and in vivo and merits further evaluation as a potential therapeutic agent for the treatment of several human leukemias.

Original languageEnglish (US)
Pages (from-to)745
Number of pages1
JournalExperimental Hematology
Volume26
Issue number8
StatePublished - 1998

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Diphtheria Toxin
Poisons
Granulocyte-Macrophage Colony-Stimulating Factor
Granulocyte-Macrophage Colony-Stimulating Factor Receptors
Cell Line
Apoptosis Regulatory Proteins
SCID Mice
Inhibitory Concentration 50
Gel Chromatography
Anions
Leukemia
Therapeutics
Bone Marrow
Escherichia coli
Proteins
In Vitro Techniques

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Hematology
  • Oncology
  • Transplantation

Cite this

Diphtheria toxin fused to human gm-csf is toxic to primary malignant progenitors from patients with AML, JMML and CMML. / Frankel, A.; Eaves, C.; Hall, P.; Kreitman, R.; Lilly, M.; Heran, M.; Bc.

In: Experimental Hematology, Vol. 26, No. 8, 1998, p. 745.

Research output: Contribution to journalArticle

Frankel, A. ; Eaves, C. ; Hall, P. ; Kreitman, R. ; Lilly, M. ; Heran, M. ; Bc. / Diphtheria toxin fused to human gm-csf is toxic to primary malignant progenitors from patients with AML, JMML and CMML. In: Experimental Hematology. 1998 ; Vol. 26, No. 8. pp. 745.
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T1 - Diphtheria toxin fused to human gm-csf is toxic to primary malignant progenitors from patients with AML, JMML and CMML

AU - Frankel, A.

AU - Eaves, C.

AU - Hall, P.

AU - Kreitman, R.

AU - Lilly, M.

AU - Heran, M.

AU - Bc,

PY - 1998

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