Multiple myeloma-related deregulation of bone marrow-derived CD34 + hematopoietic stem and progenitor cells

Ingmar Bruns, Ron Patrick Cadeddu, Ines Brueckmann, Julia Fröbel, Stefanie Geyh, Sebastian Büst, Johannes C. Fischer, Frederik Roels, Christian Matthias Wilk, Frank A. Schildberg, Ali Nuri Hünerlitürkoglu, Christoph Zilkens, Marcus Jäger, Ulrich G. Steidl, Fabian Zohren, Roland Fenk, Guido Kobbe, Benedict Brors, Akos Czibere, Thomas Schroeder & 2 others Andreas Trumpp, Rainer Haas

Research output: Contribution to journalArticle

40 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)2620-2630
Number of pages11
JournalBlood
Volume120
Issue number13
DOIs
StatePublished - Sep 27 2012

Fingerprint

Deregulation
Hematopoietic Stem Cells
Multiple Myeloma
Bone
Bone Marrow
Adhesion
Actins
Cells
Plasmas
Fluids
Extracellular Fluid
Hematopoiesis
Plasma Cells
Mesenchymal Stromal Cells
Cues
Cell Cycle

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Bruns, I., Cadeddu, R. P., Brueckmann, I., Fröbel, J., Geyh, S., Büst, S., ... Haas, R. (2012). Multiple myeloma-related deregulation of bone marrow-derived CD34 + hematopoietic stem and progenitor cells. Blood, 120(13), 2620-2630. https://doi.org/10.1182/blood-2011-04-347484

Multiple myeloma-related deregulation of bone marrow-derived CD34 + hematopoietic stem and progenitor cells. / Bruns, Ingmar; Cadeddu, Ron Patrick; Brueckmann, Ines; Fröbel, Julia; Geyh, Stefanie; Büst, Sebastian; Fischer, Johannes C.; Roels, Frederik; Wilk, Christian Matthias; Schildberg, Frank A.; Hünerlitürkoglu, Ali Nuri; Zilkens, Christoph; Jäger, Marcus; Steidl, Ulrich G.; Zohren, Fabian; Fenk, Roland; Kobbe, Guido; Brors, Benedict; Czibere, Akos; Schroeder, Thomas; Trumpp, Andreas; Haas, Rainer.

In: Blood, Vol. 120, No. 13, 27.09.2012, p. 2620-2630.

Research output: Contribution to journalArticle

Bruns, I, Cadeddu, RP, Brueckmann, I, Fröbel, J, Geyh, S, Büst, S, Fischer, JC, Roels, F, Wilk, CM, Schildberg, FA, Hünerlitürkoglu, AN, Zilkens, C, Jäger, M, Steidl, UG, Zohren, F, Fenk, R, Kobbe, G, Brors, B, Czibere, A, Schroeder, T, Trumpp, A & Haas, R 2012, 'Multiple myeloma-related deregulation of bone marrow-derived CD34 + hematopoietic stem and progenitor cells', Blood, vol. 120, no. 13, pp. 2620-2630. https://doi.org/10.1182/blood-2011-04-347484
Bruns I, Cadeddu RP, Brueckmann I, Fröbel J, Geyh S, Büst S et al. Multiple myeloma-related deregulation of bone marrow-derived CD34 + hematopoietic stem and progenitor cells. Blood. 2012 Sep 27;120(13):2620-2630. https://doi.org/10.1182/blood-2011-04-347484
Bruns, Ingmar ; Cadeddu, Ron Patrick ; Brueckmann, Ines ; Fröbel, Julia ; Geyh, Stefanie ; Büst, Sebastian ; Fischer, Johannes C. ; Roels, Frederik ; Wilk, Christian Matthias ; Schildberg, Frank A. ; Hünerlitürkoglu, Ali Nuri ; Zilkens, Christoph ; Jäger, Marcus ; Steidl, Ulrich G. ; Zohren, Fabian ; Fenk, Roland ; Kobbe, Guido ; Brors, Benedict ; Czibere, Akos ; Schroeder, Thomas ; Trumpp, Andreas ; Haas, Rainer. / Multiple myeloma-related deregulation of bone marrow-derived CD34 + hematopoietic stem and progenitor cells. In: Blood. 2012 ; Vol. 120, No. 13. pp. 2620-2630.
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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 G.

AU - Zohren, Fabian

AU - Fenk, Roland

AU - Kobbe, Guido

AU - Brors, Benedict

AU - Czibere, Akos

AU - Schroeder, Thomas

AU - Trumpp, Andreas

AU - Haas, Rainer

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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.

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