title: Inhibition of acute myelogenous leukemia progenitor proliferation by macrophage inflammatory protein 1-alpha.
abstract: Macrophage inflammatory protein-alpha (MIP-1 alpha), an 8-kDa peptide produced by stimulated macrophages, has been recently sequenced and cloned. In addition to its inflammatory effects, MIP-1 alpha inhibits proliferation of immature hematopoietic progenitors both in vitro and in vivo. Because the gene coding for MIP-1 alpha is expressed in peripheral blood cells obtained from patients with acute myelogenous leukemia (AML), we sought to evaluate the effect of MIP-1 alpha on AML precursors. We studied bone marrow samples from 21 AML patients using both the AML blast colony assay and the delta suspension culture assay. We found that recombinant human (rh) MIP-1 alpha significantly inhibits early and mature AML progenitors with sample-to-sample variability, by up to 79% at concentrations ranging from 40 to 1600 ng/ml. These results were obtained in the presence of fetal calf serum either alone or with granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, or interleukin-3. In contrast, rhMIP-1 alpha (400 ng/ml) did not significantly affect normal colony-forming unit granulocyte-macrophage (CFU-GM), or burst-forming unit-erythroid (BFU-E) proliferation. These data prompted us to delineate the inhibitory mechanism of MIP-1 alpha. Consequently, we used the thymidine suicide technique to measure DNA synthesis in AML progenitors and the enzyme-linked immunosorbent assay to quantify intracellular levels of interleukin-1 beta in AML blasts following incubation with MIP-1 alpha. We found that whereas MIP-1 alpha prevented AML progenitors from entering the proliferative phase of the cell cycle, it had no effect on interleukin-1 beta levels. Taken together, our data suggest that MIP-1 alpha may have clinical benefits in therapy for AML and should be considered for evaluation in a clinical setting.
authors.affiliation: Department of Clinical Investigation, University of Texas M.D. Anderson Cancer Center, Houston 77030.
authors.forename: A
authors.initials: A
authors.lastname: Ferrajoli
authors.forename: M
authors.initials: M
authors.lastname: Talpaz
authors.forename: T F
authors.initials: TF
authors.lastname: Zipf
authors.forename: C
authors.initials: C
authors.lastname: Hirsch-Ginsberg
authors.forename: E
authors.initials: E
authors.lastname: Estey
authors.forename: S D
authors.initials: SD
authors.lastname: Wolpe
authors.forename: Z
authors.initials: Z
authors.lastname: Estrov
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002453:Cell Cycle; D002455:Cell Division; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D002648:Child; D016207:Cytokines / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology*; D019402:Macrophage Inflammatory Proteins; D008297:Male; D008875:Middle Aged; D015846:Monokines / Q000494:pharmacology*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D011994:Recombinant Proteins / Q000494:pharmacology; D014410:Tumor Stem Cell Assay
chemical_list: D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016207:Cytokines; D007375:Interleukin-1; D019402:Macrophage Inflammatory Proteins; D015846:Monokines; D011994:Recombinant Proteins