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.
%0 Journal Article
%1 Bruns2012
%A Bruns, Ingmar
%A Cadeddu, Ron-Patrick
%A Brueckmann, Ines
%A Fröbel, Julia
%A Geyh, Stefanie
%A Büst, Sebastian
%A Fischer, Johannes C.
%A Roels, Frederik
%A Wilk, Christian Matthias
%A Schildberg, Frank A.
%A Hünerlitürkoglu, Ali-Nuri
%A Zilkens, Christoph
%A Jäger, Marcus
%A Steidl, Ulrich
%A Zohren, Fabian
%A Fenk, Roland
%A Kobbe, Guido
%A Brors, Benedict
%A Czibere, Akos
%A Schroeder, Thomas
%A Trumpp, Andreas
%A Haas, Rainer
%D 2012
%J Blood
%K Adhesion; Analysis; Animals; Antibody Antigens, Array Biological Blotting, Bone CD34, Case-Control Cell Cells, Chain Cultured; Cycle; Cytometry; Differentiation; Expression Female; Flow Fluorescent Gene Hematopoietic Humans; Immunoenzyme Inbred Male; Markers, Marrow, Megakaryocyte-Erythroid Mesenchymal Messenger, Mice, Mice; Movement; Multiple Myeloma, NOD; Oligonucleotide Polymerase Profiling; Progenitor Proliferation; RNA, Reaction; Real-Time Reverse Sequence Signal Stem Stromal Studies; Technique; Techniques; Transcriptase Transduction Western; genetics/metabolism/pathology; genetics; metabolism/pathology; metabolism;
%N 13
%P 2620--2630
%R 10.1182/blood-2011-04-347484
%T Multiple myeloma-related deregulation of bone marrow-derived CD34(+) hematopoietic stem and progenitor cells.
%U http://dx.doi.org/10.1182/blood-2011-04-347484
%V 120
%X 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.
@article{Bruns2012,
__markedentry = {[bbrors:6]},
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.},
added-at = {2015-04-09T12:36:21.000+0200},
author = {Bruns, Ingmar and Cadeddu, Ron-Patrick and Brueckmann, Ines and Fr{\"{o}}bel, Julia and Geyh, Stefanie and B{\"{u}}st, Sebastian and Fischer, Johannes C. and Roels, Frederik and Wilk, Christian Matthias and Schildberg, Frank A. and H{\"{u}}nerlit{\"{u}}rkoglu, Ali-Nuri and Zilkens, Christoph and J{\"{a}}ger, Marcus and Steidl, Ulrich and Zohren, Fabian and Fenk, Roland and Kobbe, Guido and Brors, Benedict and Czibere, Akos and Schroeder, Thomas and Trumpp, Andreas and Haas, Rainer},
biburl = {https://www.bibsonomy.org/bibtex/2b04528a29fac6128e99649ee391429f1/bbrors},
doi = {10.1182/blood-2011-04-347484},
institution = {Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University, Düsseldorf, Germany. brunsin@med.uni-duesseldorf.de},
interhash = {da3587e22363b7d5414a3a2a4227cc39},
intrahash = {b04528a29fac6128e99649ee391429f1},
journal = {Blood},
keywords = {Adhesion; Analysis; Animals; Antibody Antigens, Array Biological Blotting, Bone CD34, Case-Control Cell Cells, Chain Cultured; Cycle; Cytometry; Differentiation; Expression Female; Flow Fluorescent Gene Hematopoietic Humans; Immunoenzyme Inbred Male; Markers, Marrow, Megakaryocyte-Erythroid Mesenchymal Messenger, Mice, Mice; Movement; Multiple Myeloma, NOD; Oligonucleotide Polymerase Profiling; Progenitor Proliferation; RNA, Reaction; Real-Time Reverse Sequence Signal Stem Stromal Studies; Technique; Techniques; Transcriptase Transduction Western; genetics/metabolism/pathology; genetics; metabolism/pathology; metabolism;},
language = {eng},
medline-pst = {ppublish},
month = Sep,
number = 13,
owner = {bbrors},
pages = {2620--2630},
pii = {blood-2011-04-347484},
pmid = {22517906},
timestamp = {2015-04-09T12:36:21.000+0200},
title = {Multiple myeloma-related deregulation of bone marrow-derived CD34(+) hematopoietic stem and progenitor cells.},
url = {http://dx.doi.org/10.1182/blood-2011-04-347484},
volume = 120,
year = 2012
}