title: Granulocyte-colony stimulating factor, granulocyte-macrophage colony stimulating factor, PIXY-321, stem cell factor, interleukin-3, and interleukin-7: receptor binding and effects on clonogenic proliferation in acute lymphoblastic leukemia.
abstract: Cytokines are frequently used after chemotherapy of leukemias and solid tumors to augment recovery of normal hematopoiesis. While the regulation of normal and leukemic myelopoiesis is well investigated, little is known about effects of cytokines on growth and differentiation of lymphoblastic leukemia. In this study, we investigated the expression of receptors for G-CSF, GM-CSF, SCF, IL-3, and IL-7 on acute lymphoblastic leukemia (ALL) blasts and the effects of these growth factors (GF) on ALL blast colony formation. The binding of fluorescence-tagged cytokines to receptors on ALL blasts was studied by flow-cytometry in 27 cases of ALL (24 precursor B-ALL, 3 T-ALL). Receptor-binding for myeloid-associated GF was observed in the majority of precursor B-ALL (G-CSF = 100%, GM-CSF = 65%, IL-3 = 83%, SCF = 74%), but not in T-ALL. Binding of labelled IL-7 was detected in both precursor B- (92%) and T-ALL (100%). The presence of receptors for SCF in ALL was confirmed by polymerase chain reaction for c-kit mRNA in 19/21 cases tested. Expression of receptors for G-CSF, GM-CSF, IL-3, and SCF was not associated with expression of myeloid antigens, or with specific cytogenetic abnormalities. The effects of these GF on clonogenic cells were tested in the ALL blast colony assay and varied between samples, but all cytokines were able to increase clonogenic growth. The GM-CSF/IL-3 fusion molecule PIXY-321 was most effective in promoting colony growth. In some cases inhibition of colony formation was found. We conclude that ALL blast cells have receptors not only for IL-7, but also for G-CSF, GM-CSF, SCF, and IL-3. ALL precursors can respond to these GF with changes in their clonogenic growth indicating the presence of functional receptors. Results may have implications for therapeutic approaches combining cytokines and chemotherapy.
authors.affiliation: Department of Hematology, University of Texas M. D. Anderson Cancer Center, Houston.
authors.forename: D
authors.initials: D
authors.lastname: Drach
authors.forename: Z
authors.initials: Z
authors.lastname: Estrov
authors.forename: S
authors.initials: S
authors.lastname: Zhao
authors.forename: J
authors.initials: J
authors.lastname: Drach
authors.forename: A
authors.initials: A
authors.lastname: Cork
authors.forename: D
authors.initials: D
authors.lastname: Collins
authors.forename: H
authors.initials: H
authors.lastname: Kantarjian
authors.forename: M
authors.initials: M
authors.lastname: Andreeff
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000032:analysis; D002051:Burkitt Lymphoma / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism* / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism* / Q000494:pharmacology*; D016298:Hematopoietic Cell Growth Factors / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D007377:Interleukin-3 / Q000378:metabolism* / Q000494:pharmacology*; D015851:Interleukin-7 / Q000378:metabolism* / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit; D012333:RNA, Messenger / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D016184:Receptors, Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000378:metabolism*; D016185:Receptors, Interleukin-3 / Q000378:metabolism*; D020395:Receptors, Interleukin-7; D011993:Recombinant Fusion Proteins / Q000378:metabolism* / Q000494:pharmacology*; D019089:Stem Cell Factor
chemical_list: D000951:Antigens, Neoplasm; D016298:Hematopoietic Cell Growth Factors; D007377:Interleukin-3; D015851:Interleukin-7; C078524:PIXY321 fusion protein, recombinant; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016184:Receptors, Colony-Stimulating Factor; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D018123:Receptors, Interleukin; D016185:Receptors, Interleukin-3; D020395:Receptors, Interleukin-7; D011993:Recombinant Fusion Proteins; D019089:Stem Cell Factor; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases