title: Activation of the complement cascade enhances motility of leukemic cells by downregulating expression of HO-1.
abstract: As a crucial arm of innate immunity, the complement cascade (ComC) is involved both in mobilization of normal hematopoietic stem/progenitor cells (HSPCs) from bone marrow (BM) into peripheral blood and in their homing to BM. Despite the fact that ComC cleavage fragments alone do not chemoattract normal HSPCs, we found that leukemia cell lines as well as clonogenic blasts from chronic myeloid leukemia and acute myeloid leukemia patients respond robustly to C3 and C5 cleavage fragments by chemotaxis and increased adhesion. This finding was supported by the detection of C3a and C5a receptors in cells from human malignant hematopoietic cell lines and patient blasts at the mRNA (reverse transcriptase-polymerase chain reaction) and protein level (fluorescence-activated cell sorting), and by the demonstration that these receptors respond to stimulation by C3a and C5a by phosphorylation of p42/44 and p38 mitogen-activated protein kinases (MAPK), and protein kinase B (PKB/AKT). We also found that inducible heme oxygenase 1 (HO-1) is a negative regulator of ComC-mediated trafficking of leukemic cells, and that stimulation of leukemic cells by C3 or C5 cleavage fragments activates p38 MAPK, which downregulates HO-1 expression, rendering cells more mobile. We conclude that activation of the ComC in leukemia/lymphoma patients (for example, as a result of accompanying infections) enhances the motility of malignant cells and contributes to their spread in a p38 MAPK-HO-1-dependent manner. Therefore, inhibition of p38 MAPK or upregulation of HO-1 by small-molecule modulators would have a beneficial effect on ameliorating cell migration-mediated expansion of leukemia/lymphoma cells when the ComC becomes activated.
authors.affiliation: Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Abdelbaset-Ismail
authors.affiliation: Department of Physiology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: S
authors.initials: S
authors.lastname: Borkowska-Rzeszotek
authors.affiliation: Department of Physiology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: E
authors.initials: E
authors.lastname: Kubis
authors.affiliation: Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.
authors.forename: K
authors.initials: K
authors.lastname: Bujko
authors.affiliation: Department of Hematology, Multi-Specialist Hospital, Gorzow Wielkopolski, Poland.
authors.forename: K
authors.initials: K
authors.lastname: Brzeźniakiewicz-Janus
authors.affiliation: Department of Regenerative Medicine, Medical University of Bialystok, Bialystok, Poland.|Department of Hematology, Medical University of Bialystok, Bialystok, Poland.
authors.forename: L
authors.initials: L
authors.lastname: Bolkun
authors.affiliation: Department of Regenerative Medicine, Medical University of Bialystok, Bialystok, Poland.|Department of Hematology, Medical University of Bialystok, Bialystok, Poland.
authors.forename: J
authors.initials: J
authors.lastname: Kloczko
authors.affiliation: Department of Regenerative Medicine, Medical University of Bialystok, Bialystok, Poland.
authors.forename: M
authors.initials: M
authors.lastname: Moniuszko
authors.affiliation: Department of Hematology, Warsaw Medical University, Warsaw, Poland.
authors.forename: G W
authors.initials: GW
authors.lastname: Basak
authors.affiliation: Department of Hematology, Warsaw Medical University, Warsaw, Poland.
authors.forename: W
authors.initials: W
authors.lastname: Wiktor-Jedrzejczak
authors.affiliation: Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.|Department of Regenerative Medicine, Warsaw Medical University, Warsaw, Poland.
authors.forename: M Z
authors.initials: MZ
authors.lastname: Ratajczak
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D002633:Chemotaxis / Q000235:genetics / Q000276:immunology; D003167:Complement Activation / Q000276:immunology*; D003176:Complement C3 / Q000276:immunology / Q000378:metabolism; D003182:Complement C5 / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation; D005434:Flow Cytometry; D015973:Gene Expression Regulation, Leukemic; D055786:Gene Knockout Techniques; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics*; D064593:Heterografts; D006801:Humans; D016130:Immunophenotyping; D007938:Leukemia / Q000235:genetics* / Q000276:immunology*; D051379:Mice; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics; D044087:Receptor, Anaphylatoxin C5a / Q000235:genetics / Q000378:metabolism; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000378:metabolism; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D003176:Complement C3; D003182:Complement C5; D034741:RNA, Small Interfering; D044087:Receptor, Anaphylatoxin C5a; D063268:Sialic Acid Binding Ig-like Lectin 3; D051547:Heme Oxygenase-1; D048051:p38 Mitogen-Activated Protein Kinases