Interleukin-4 variant (BAY 36-1677) selectively induces apoptosis in acute lymphoblastic leukemia cells.
Interleukin 4 (IL-4) suppresses the growth of acute lymphoblastic leukemia (ALL) cells, but its clinical usefulness is limited by proinflammatory activity due mainly to the interaction of cytokine with endothelial cells and fibroblasts. Stroma-supported cultures of leukemic lymphoblasts were used to test the antileukemic activity of an IL-4 variant, BAY 36-1677, in which the mutations Arg 121 to Glu and Thr 13 to Asp ensure high affinity for IL-4Ralpha/IL-2Rgamma receptors expressed by lymphoid cells, without activation of the IL-4Ralpha/IL-13Ralpha receptors mainly expressed by other cells. BAY 36-1677 (25 ng/mL) was cytotoxic in 14 of 16 cases of B-lineage ALL; the median reduction in cell recovery after 7 days of culture was 85% (range, 17%-95%) compared to results of parallel cultures not exposed to the cytokine. Twelve of the 14 sensitive cases had t(9;22) or 11q23 abnormalities; 3 were obtained at relapse. BAY 36-1677 induced apoptosis in leukemic lymphoblasts but did not substantially affect the growth of normal CD34+ cells, thus conferring a growth advantage to normal hematopoietic cells over leukemic lymphoblasts in vitro. BAY 36-1677 had antileukemic activity equal or superior to that produced by native IL-4, but it lacked any effects on the growth of endothelial cells and fibroblasts. The molecular manipulation of IL-4 to abrogate its proinflammatory activity has generated a novel and therapeutically promising cytokine for the treatment of high-risk ALL.
Srivannaboon
K
K
Departments of Hematology-Oncology and Pathology, St Jude Children's Research Hospital, and the University of Tennessee College of Medicine, Memphis, TN, USA.
Shanafelt
A B
AB
Todisco
E
E
Forte
C P
CP
Behm
F G
FG
Raimondi
S C
SC
Pui
C H
CH
Campana
D
D
D000293:Adolescent; D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004354:Drug Screening Assays, Antitumor; D004727:Endothelium / Q000166:cytology / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007223:Infant; D015847:Interleukin-4 / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use*; D016297:Mutagenesis, Site-Directed; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000473:pathology*; D017433:Protein Structure, Secondary; D017154:Stromal Cells / Q000502:physiology; D014407:Tumor Cells, Cultured
C421402:interleukin-4 variant; D015847:Interleukin-4