Expression of interleukin-3 receptor subunits on defined subpopulations of acute myeloid leukemia blasts predicts the cytotoxicity of diphtheria toxin interleukin-3 fusion protein against malignant progenitors that engraft in immunodeficient mice.

Abstract

The interleukin-3 receptor (IL-3R) subunits are overexpressed on acute myeloid leukemia (AML) blasts compared with normal hematopoietic cells and are thus potential targets for novel therapeutic agents. Both fluorescence-activated cell sorter (FACS) analysis and quantitative real-time reverse transcription-polymerase chain reaction (QRT-PCR) were used to quantify expression of the IL-3Ralpha and beta(c) subunits on AML cells. QRT-PCR for both subunits was most predictive of killing of AML colony-forming cells (AML-CFCs) by diphtheria toxin-IL-3 fusion protein (DT(388)IL3). Among 19 patient samples, the relative level of the IL-3Ralpha was higher than the IL-3Rbeta(c) and highest in CD34(+)CD38(-)CD71(-) cells, enriched for candidate leukemia stem cells, compared with cell fractions depleted of such progenitors. Overall, the amount of IL-3Rbeta(c) subunit did not vary among sorted subpopulations. However, expression of both subunits varied by more than 10-fold among different AML samples for all subpopulations studied. The level of IL-3Rbeta(c) expression versus glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (set at 1000) ranged from 0.14 to 13.56 in CD34(+)CD38(-)CD71(-) cells from different samples; this value was correlated (r = .76, P = .05) with the ability of DT(388)IL3 to kill AML progenitors that engraft in beta(2)-microglobin-deficient nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice (n = 7). Thus, quantification of IL-3R subunit expression on AML blasts predicts the effectiveness IL-3R-targeted therapy in killing primitive leukemic progenitors.

• Authors: Leman Yalcintepe, Arthur E Frankel, Donna E Hogge
• Journal: Blood (Blood) Vol. 108 Issue 10 Pg. 3530-7 (Nov 15 2006) ISSN: 0006-4971 [Print] United States
• PMID: 16882709 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Cytokine Receptor Common beta Subunit
• Diphtheria Toxin
• IL3RA protein, human
• Interleukin-3 Receptor alpha Subunit
• Neoplasm Proteins
• Receptors, Interleukin-3
• Recombinant Fusion Proteins

Topics

• Acute Disease
• Adolescent
• Adult
• Aged
• Animals
• Antineoplastic Agents (administration & dosage)
• Blast Crisis (pathology)
• Cytokine Receptor Common beta Subunit (analysis)
• Diphtheria Toxin (therapeutic use)
• Drug Delivery Systems
• Female
• Humans
• Immunophenotyping
• Interleukin-3 Receptor alpha Subunit (analysis)
• Leukemia, Myeloid (diagnosis, drug therapy, pathology)
• Male
• Mice
• Mice, SCID
• Middle Aged
• Neoplasm Proteins (analysis)
• Neoplasms, Experimental
• Neoplastic Stem Cells (transplantation)
• Predictive Value of Tests
• Prognosis
• Receptors, Interleukin-3 (analysis)
• Recombinant Fusion Proteins (therapeutic use)