title: Effects of FLT3 ligand on human leukemia cells. I. Proliferative response of myeloid leukemia cells.
abstract: The growth of cells in vitro and in vivo is regulated by several environmental signals among which growth factors (cytokines) figure prominently. FLT3 is a novel cytokine receptor with intrinsic ligand-stimulated (FLT3 ligand, FL) tyrosine kinase activity. Here, using a specific anti-FLT3 monoclonal antibody (McAb) and flow cytometry we determined the expression pattern of the receptor protein in 55 human leukemia-lymphoma cell lines and in 20 primary samples from patients with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). FLT3 receptor surface expression was found predominantly in pre-B cell, myeloid and monocytic cell lines and in pre-B-ALL and AML cells, FL was overexpressed in baby hamster kidney cells producing a recombinant protein that was functional in receptor binding and signaling. Incubation with FL induced 3H-thymidine uptake-measured proliferation in some myeloid cell lines and in 2/9 AML cases. The strongest proliferative response was seen in the two growth factor-dependent myeloid leukemia cell lines MUTZ-2 and OCI-AML-5. Long-term substitution of the commonly used cytokines with FL sustained the continuous proliferation of these two cell lines suggesting that also upon permanent activation FLT2 can function as a mitogenic signaling molecule. Despite the high density of FLT3 receptor expression on cultured and fresh pre-B-ALL cells, no proliferation could be stimulated in any of these specimens. Incubation with the anti-FLT3 McAb had agonistic proliferative effects in MUTZ-2 and OCI-AML-5; and anti-FL reagent blocked FL-stimulated proliferation. To summarize, we demonstrated that FL is effective in inducing proliferation of leukemic myeloid cells and that protein expression does not necessarily indicate an FL-responsive cell. While the present data clearly demonstrate that FL might play a proliferative role in leukemogenesis, further studies are needed to clarify whether the signals provided by FL:FLT3 interaction are confined to a proliferation-inducing function or whether maturational progression could also be elicited in certain cells.
authors.affiliation: Department of Human and Animal Cell Cultures, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Dehmel
authors.forename: M
authors.initials: M
authors.lastname: Zaborski
authors.forename: G
authors.initials: G
authors.lastname: Meierhoff
authors.forename: O
authors.initials: O
authors.lastname: Rosnet
authors.forename: D
authors.initials: D
authors.lastname: Birnbaum
authors.forename: W D
authors.initials: WD
authors.lastname: Ludwig
authors.forename: H
authors.initials: H
authors.lastname: Quentmeier
authors.forename: H G
authors.initials: HG
authors.lastname: Drexler
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal; D015152:Blotting, Northern; D002455:Cell Division; D002648:Child; D002675:Child, Preschool; D006224:Cricetinae; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007223:Infant; D007938:Leukemia / Q000378:metabolism* / Q000473:pathology; D007951:Leukemia, Myeloid / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D008875:Middle Aged; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000473:pathology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D008565:Membrane Proteins; C084881:flt3 ligand protein; D020794:Receptor Protein-Tyrosine Kinases