title: Further evidence that paroxysmal nocturnal haemoglobinuria is a disorder of defective cell membrane lipid rafts.
abstract: The glycolipid glycosylphosphatidylinositol anchor (GPI-A) plays an important role in lipid raft formation, which is required for proper expression on the cell surface of two inhibitors of the complement cascade, CD55 and CD59. The absence of these markers from the surface of blood cells, including erythrocytes, makes the cells susceptible to complement lysis, as seen in patients suffering from paroxysmal nocturnal haemoglobinuria (PNH). However, the explanation for why PNH-affected hematopoietic stem/progenitor cells (HSPCs) expand over time in BM is still unclear. Here, we propose an explanation for this phenomenon and provide evidence that a defect in lipid raft formation in HSPCs leads to defective CXCR4- and VLA-4-mediated retention of these cells in BM. In support of this possibility, BM-isolated CD34(+) cells from PNH patients show a defect in the incorporation of CXCR4 and VLA-4 into membrane lipid rafts, respond weakly to SDF-1 stimulation, and show defective adhesion to fibronectin. Similar data were obtained with the GPI-A(-) Jurkat cell line. Moreover, we also report that chimeric mice transplanted with CD55(-/-)  CD59(-/-) BM cells but with proper GPI-A expression do not expand over time in transplanted hosts. On the basis of these findings, we propose that a defect in lipid raft formation in PNH-mutated HSPCs makes these cells more mobile, so that they expand and out-compete normal HSPCs from their BM niches over time.
authors.affiliation: Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.|Department of Regenerative Medicine, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Mariusz Z
authors.initials: MZ
authors.lastname: Ratajczak
authors.affiliation: Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.
authors.forename: Sylwia
authors.initials: S
authors.lastname: Borkowska
authors.affiliation: Department of Physiology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: Kasia
authors.initials: K
authors.lastname: Mierzejewska
authors.affiliation: Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.|Department of Regenerative Medicine, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Magda
authors.initials: M
authors.lastname: Kucia
authors.affiliation: Central Clinical Hospital MSW, Poland and Medical University of Warsaw, Warsaw, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Mendek-Czajkowska
authors.affiliation: Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.
authors.forename: Malwina
authors.initials: M
authors.lastname: Suszynska
authors.affiliation: Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.
authors.forename: Vivek A
authors.initials: VA
authors.lastname: Sharma
authors.affiliation: Central Clinical Hospital MSW, Poland and Medical University of Warsaw, Warsaw, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Deptala
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Wechao
authors.initials: W
authors.lastname: Song
authors.affiliation: Universitaetsklinikum Carl-Gustav-Carus, Dresden, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Platzbecker
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, AB, Canada.
authors.forename: Loree
authors.initials: L
authors.lastname: Larratt
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, AB, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Janowska-Wieczorek
authors.affiliation: Tausig Cancer Center, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Jarek
authors.initials: J
authors.lastname: Maciejewski
authors.affiliation: Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.
authors.forename: Janina
authors.initials: J
authors.lastname: Ratajczak
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001427:Bacterial Toxins / Q000378:metabolism; D001853:Bone Marrow / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D005353:Fibronectins / Q000378:metabolism; D017261:Glycosylphosphatidylinositols / Q000378:metabolism; D006457:Hemoglobinuria, Paroxysmal / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D039041:Integrin alpha4beta1 / Q000378:metabolism; D019169:Jurkat Cells; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D052899:Pore Forming Cytotoxic Proteins / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D015703:Antigens, CD; D001427:Bacterial Toxins; D054377:Chemokine CXCL12; D005353:Fibronectins; D017261:Glycosylphosphatidylinositols; D039041:Integrin alpha4beta1; D052899:Pore Forming Cytotoxic Proteins; D019718:Receptors, CXCR4; C032676:aerolysin
keywords: CXCR4; PNH; S1P; complement; lipid rafts