PUBLICATION
Luspatercept restores SDF-1-mediated hematopoietic support by MDS-derived mesenchymal stromal cells
- Authors
- Wobus, M., Mies, A., Asokan, N., Oelschlägel, U., Möbus, K., Winter, S., Cross, M., Weidner, H., Rauner, M., Hofbauer, L.C., Bornhäuser, M., Platzbecker, U.
- ID
- ZDB-PUB-210519-25
- Date
- 2021
- Source
- Leukemia 35(10): 2936-2947 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Activin Receptors, Type II/pharmacology*
- Adult
- Aged
- Animals
- Case-Control Studies
- Chemokine CXCL12/genetics
- Chemokine CXCL12/metabolism*
- Hematinics/pharmacology
- Hematopoiesis*
- Hematopoietic Stem Cells/drug effects*
- Hematopoietic Stem Cells/metabolism
- Hematopoietic Stem Cells/pathology
- Humans
- Immunoglobulin Fc Fragments/pharmacology*
- Mesenchymal Stem Cells/drug effects*
- Mesenchymal Stem Cells/metabolism
- Mesenchymal Stem Cells/pathology
- Middle Aged
- Myelodysplastic Syndromes/drug therapy*
- Myelodysplastic Syndromes/metabolism
- Myelodysplastic Syndromes/pathology
- Recombinant Fusion Proteins/pharmacology*
- Smad2 Protein/genetics
- Smad2 Protein/metabolism
- Tumor Cells, Cultured
- Zebrafish
- PubMed
- 34002031 Full text @ Leukemia
Citation
Wobus, M., Mies, A., Asokan, N., Oelschlägel, U., Möbus, K., Winter, S., Cross, M., Weidner, H., Rauner, M., Hofbauer, L.C., Bornhäuser, M., Platzbecker, U. (2021) Luspatercept restores SDF-1-mediated hematopoietic support by MDS-derived mesenchymal stromal cells. Leukemia. 35(10):2936-2947.
Abstract
The bone marrow microenvironment (BMME) plays a key role in the pathophysiology of myelodysplastic syndromes (MDS), clonal blood disorders affecting the differentiation, and maturation of hematopoietic stem and progenitor cells (HSPCs). In lower-risk MDS patients, ineffective late-stage erythropoiesis can be restored by luspatercept, an activin receptor type IIB ligand trap. Here, we investigated whether luspatercept can modulate the functional properties of mesenchymal stromal cells (MSCs) as key components of the BMME. Luspatercept treatment inhibited Smad2/3 phosphorylation in both healthy and MDS MSCs and reversed disease-associated alterations in SDF-1 secretion. Pre-treatment of MDS MSCs with luspatercept restored the subsequent clonogenic potential of co-cultured HSPCs and increased both their stromal-adherence and their expression of both CXCR4 and ß3 integrin. Luspatercept pre-treatment of MSCs also increased the subsequent homing of co-cultured HSPCs in zebrafish embryos. MSCs derived from patients who had received luspatercept treatment had an increased capacity to maintain the colony forming potential of normal but not MDS HSPCs. These data provide the first evidence that luspatercept impacts the BMME directly, leading to a selective restoration of the ineffective hematopoiesis that is a hallmark of MDS.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping