title: Multiple myeloma-related deregulation of bone marrow-derived CD34(+) hematopoietic stem and progenitor cells.
abstract: Multiple myeloma (MM) is a clonal plasma cell disorder frequently accompanied by hematopoietic impairment. We show that hematopoietic stem and progenitor cells (HSPCs), in particular megakaryocyte-erythrocyte progenitors, are diminished in the BM of MM patients. Genomic profiling of HSPC subsets revealed deregulations of signaling cascades, most notably TGFβ signaling, and pathways involved in cytoskeletal organization, migration, adhesion, and cell-cycle regulation in the patients. Functionally, proliferation, colony formation, and long-term self-renewal were impaired as a consequence of activated TGFβ signaling. In accordance, TGFβ levels in the BM extracellular fluid were elevated and mesenchymal stromal cells (MSCs) had a reduced capacity to support long-term hematopoiesis of HSPCs that completely recovered on blockade of TGFβ signaling. Furthermore, we found defective actin assembly and down-regulation of the adhesion receptor CD44 in MM HSPCs functionally reflected by impaired migration and adhesion. Still, transplantation into myeloma-free NOG mice revealed even enhanced engraftment and normal differentiation capacities of MM HSPCs, which underlines that functional impairment of HSPCs depends on MM-related microenvironmental cues and is reversible. Taken together, these data implicate that hematopoietic suppression in MM emerges from the HSPCs as a result of MM-related microenvironmental alterations.
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University, Düsseldorf, Germany. brunsin@med.uni-duesseldorf.de
authors.forename: Ingmar
authors.initials: I
authors.lastname: Bruns
authors.forename: Ron-Patrick
authors.initials: RP
authors.lastname: Cadeddu
authors.forename: Ines
authors.initials: I
authors.lastname: Brueckmann
authors.forename: Julia
authors.initials: J
authors.lastname: Fröbel
authors.forename: Stefanie
authors.initials: S
authors.lastname: Geyh
authors.forename: Sebastian
authors.initials: S
authors.lastname: Büst
authors.forename: Johannes C
authors.initials: JC
authors.lastname: Fischer
authors.forename: Frederik
authors.initials: F
authors.lastname: Roels
authors.forename: Christian Matthias
authors.initials: CM
authors.lastname: Wilk
authors.forename: Frank A
authors.initials: FA
authors.lastname: Schildberg
authors.forename: Ali-Nuri
authors.initials: AN
authors.lastname: Hünerlitürkoglu
authors.forename: Christoph
authors.initials: C
authors.lastname: Zilkens
authors.forename: Marcus
authors.initials: M
authors.lastname: Jäger
authors.forename: Ulrich
authors.initials: U
authors.lastname: Steidl
authors.forename: Fabian
authors.initials: F
authors.lastname: Zohren
authors.forename: Roland
authors.initials: R
authors.lastname: Fenk
authors.forename: Guido
authors.initials: G
authors.lastname: Kobbe
authors.forename: Benedict
authors.initials: B
authors.lastname: Brors
authors.forename: Akos
authors.initials: A
authors.lastname: Czibere
authors.forename: Thomas
authors.initials: T
authors.lastname: Schroeder
authors.forename: Andreas
authors.initials: A
authors.lastname: Trumpp
authors.forename: Rainer
authors.initials: R
authors.lastname: Haas
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism*; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D002448:Cell Adhesion; D002453:Cell Cycle; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D055015:Megakaryocyte-Erythroid Progenitor Cells / Q000378:metabolism / Q000473:pathology*; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D018952:Antigens, CD34; D015415:Biomarkers; D012333:RNA, Messenger