title: Human recombinant interferon-inducible protein-10 inhibits the proliferation of normal and acute myelogenous leukemia progenitors.
abstract: Recombinant human interferon-inducible protein-10 (rIP-10) has been recently identified, purified and shown to suppress the multiplication of normal marrow early hemopoietic progenitors. In the present study we investigated the effect of rIP-10 on different normal and acute myelogenous leukemia (AML) progenitor populations. We first studied hematologically normal bone marrow using the delta culture assay, in which marrow low-density cells were incubated in liquid culture with recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) for 1 week, to allow the differentiation of mature progenitors, and thereafter cultured in methylcellulose in the presence of rGM-CSF and recombinant erythropoietin (rEPO). In this assay rIP-10 significantly inhibited the proliferation of normal marrow hemopoietic progenitors in a dose-dependent fashion. However, when fresh normal marrow cells were cultured in methylcellulose without preincubation in liquid culture, rIP-10 did not affect the growth of colony-forming cells. In contrast, when recombinant c-kit ligand (rKL) was added to rGM-CSF and rEPO, an increment in colony numbers was observed that was eliminated by rIP-10. Similar experiments performed with low-density, non-adherent, T cell-depleted AML marrow cells, obtained from 12 untreated adult AML patients, revealed qualitatively similar results: rIP-10 inhibited the proliferation of AML progenitors in the AML delta assay but did not affect the growth of rGM-CSF-responsive AML colony-forming cells when plated in semisolid media in the presence of rGM-CSF. When rKL was added to rGM-CSF during plating in an effort to recruit additional AML progenitor populations, there was an increment in leukemic blast colony numbers that was eliminated by rIP-10. As observed with normal progenitors, the effect of rIP-10 on these AML progenitors was concentration-dependent, statistically significant and reversible with a rIP-10-neutralizing antiserum. To delineate the mechanism of action of rIP-10 we used the thymidine suicide assay and found that rIP-10 significantly reduced the fraction of leukemic progenitors synthesizing DNA. Our data suggest the rIP-10 inhibits the proliferation of (probably immature) AML progenitor populations by reducing the fraction of cells undergoing DNA synthesis. Additional studies are needed to further elucidate the mechanism of this inhibition and to determine the potential clinical benefits of rIP-10 in future therapies for AML.
authors.affiliation: Department of Hematology, University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: A H
authors.initials: AH
authors.lastname: Sarris
authors.forename: M
authors.initials: M
authors.lastname: Talpaz
authors.forename: A B
authors.initials: AB
authors.lastname: Deisseroth
authors.forename: Z
authors.initials: Z
authors.lastname: Estrov
mesh_terms: D000208:Acute Disease; D000368:Aged; D015703:Antigens, CD / Q000032:analysis; D018952:Antigens, CD34 / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D018826:CD13 Antigens / Q000032:analysis; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D003114:Colony-Forming Units Assay; D016207:Cytokines / Q000494:pharmacology*; D004921:Erythropoietin / Q000494:pharmacology; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007951:Leukemia, Myeloid / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D011994:Recombinant Proteins / Q000494:pharmacology; D063268:Sialic Acid Binding Ig-like Lectin 3; D019089:Stem Cell Factor / Q000494:pharmacology; D014410:Tumor Stem Cell Assay
chemical_list: D015703:Antigens, CD; D018952:Antigens, CD34; D015214:Antigens, Differentiation, Myelomonocytic; C571163:CD33 protein, human; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D016207:Cytokines; D006131:Growth Inhibitors; D011994:Recombinant Proteins; D063268:Sialic Acid Binding Ig-like Lectin 3; D019089:Stem Cell Factor; D004921:Erythropoietin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D018826:CD13 Antigens