title: Diphtheria toxin fused to variant human interleukin-3 induces cytotoxicity of blasts from patients with acute myeloid leukemia according to the level of interleukin-3 receptor expression.
abstract: Leukemic blasts from patients with acute myeloid leukemia (AML) frequently express high levels of the interleukin-3 receptor alpha chain (IL-3Ralpha). In the present study, we have explored the sensitivity of primary leukemic blasts obtained from 34 patients with AML to a diphtheria toxin (DT) composed of the catalytic and translocation domains of DT (DT388) fused to IL-3 (DT388IL-3) and to DT388 fused to a variant IL-3 with increased binding affinity (DT388IL-3[K116W]). On a molar basis, DT388IL-3[K116W] was significantly more active than DT388IL-3 in mediating leukemic cell killing. The rate of cell killing induced by the 2 DT/IL-3 fusion proteins was significantly correlated with the level of IL-3Ralpha/IL-3Rbeta expressed on leukemic blasts. These observations support a potential use of DT388IL-3[K116W] in the treatment of refractory AMLs and provide a simple biochemical parameter for the selection of eligible patients.
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, University La Sapienza, Rome, Italy. u.testa@iss.it
authors.forename: Ugo
authors.initials: U
authors.lastname: Testa
authors.forename: Roberta
authors.initials: R
authors.lastname: Riccioni
authors.forename: Mauro
authors.initials: M
authors.lastname: Biffoni
authors.forename: Daniela
authors.initials: D
authors.lastname: Diverio
authors.forename: Francesco
authors.initials: F
authors.lastname: Lo-Coco
authors.forename: Robin
authors.initials: R
authors.lastname: Foà
authors.forename: Cesare
authors.initials: C
authors.lastname: Peschle
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Frankel
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001665:Binding Sites; D001854:Bone Marrow Cells / Q000166:cytology; D020134:Catalytic Domain; D004167:Diphtheria Toxin / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006133:Growth Substances / Q000378:metabolism; D006801:Humans; D007377:Interleukin-3 / Q000737:chemistry* / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000628:therapy*; D011379:Prognosis; D017434:Protein Structure, Tertiary; D016185:Receptors, Interleukin-3 / Q000096:biosynthesis*; D011993:Recombinant Fusion Proteins / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D004167:Diphtheria Toxin; D006133:Growth Substances; D007377:Interleukin-3; D016185:Receptors, Interleukin-3; D011993:Recombinant Fusion Proteins