TY - JOUR
T1 - Multiple myeloma-related deregulation of bone marrow-derived CD34 + hematopoietic stem and progenitor cells
AU - Bruns, Ingmar
AU - Cadeddu, Ron Patrick
AU - Brueckmann, Ines
AU - Fröbel, Julia
AU - Geyh, Stefanie
AU - Büst, Sebastian
AU - Fischer, Johannes C.
AU - Roels, Frederik
AU - Wilk, Christian Matthias
AU - Schildberg, Frank A.
AU - Hünerlitürkoglu, Ali Nuri
AU - Zilkens, Christoph
AU - Jäger, Marcus
AU - Steidl, Ulrich
AU - Zohren, Fabian
AU - Fenk, Roland
AU - Kobbe, Guido
AU - Brors, Benedict
AU - Czibere, Akos
AU - Schroeder, Thomas
AU - Trumpp, Andreas
AU - Haas, Rainer
PY - 2012/9/27
Y1 - 2012/9/27
N2 - 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 megakaryocyteerythrocyte progenitors, are diminished in the BM of MM patients. Genomic profiling of HSPC subsets revealed deregulations of signaling cascades, most notably TGF- signaling, and pathways involved in cytoskeletal organization, migration, adhesion, and cell-cycle regulation in the patients. Functionally, proliferation, colony formation, and long-term selfrenewal were impaired as a consequence of activated TGF- signaling. In accordance, TGF- 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 TGF- 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 myelomafree 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.
AB - 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 megakaryocyteerythrocyte progenitors, are diminished in the BM of MM patients. Genomic profiling of HSPC subsets revealed deregulations of signaling cascades, most notably TGF- signaling, and pathways involved in cytoskeletal organization, migration, adhesion, and cell-cycle regulation in the patients. Functionally, proliferation, colony formation, and long-term selfrenewal were impaired as a consequence of activated TGF- signaling. In accordance, TGF- 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 TGF- 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 myelomafree 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.
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U2 - 10.1182/blood-2011-04-347484
DO - 10.1182/blood-2011-04-347484
M3 - Article
C2 - 22517906
AN - SCOPUS:84866856496
SN - 0006-4971
VL - 120
SP - 2620
EP - 2630
JO - Blood
JF - Blood
IS - 13
ER -