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Neuropilin2 in Mesenchymal Stromal Cells as a Potential Novel Therapeutic Target in Myelofibrosis
Karla Vosbeck1, Sarah Förster1, Thomas Mayr1
1Institute for Pathology, University Hospital Bonn, 53127 Bonn, Germany.
Abstract:
Bone marrow fibrosis in myeloproliferative neoplasm (MPN), myelodysplastic syndromes (MDS), MPN/MDS overlap syndromes and acute myeloid leukemia (AML) is associated with poor prognosis and early treatment failure. Myelofibrosis (MF) is accompanied by reprogramming of multipotent bone marrow mesenchymal stromal cells (MSC) into osteoid and fiber-producing stromal cells. We demonstrate NRP2 and osteolineage marker NCAM1 (neural cell adhesion molecule 1) expression within the endosteal niche in normal bone marrow and aberrantly in MPN, MDS MPN/MDS overlap syndromes and AML (n = 99), as assessed by immunohistochemistry. Increased and diffuse expression in mesenchymal stromal cells and osteoblasts correlates with high MF grade in MPN (p < 0.05 for NRP2 and NCAM1). Single cell RNA sequencing (scRNAseq) re-analysis demonstrated NRP2 expression in endothelial cells and partial co-expression of NRP2 and NCAM1 in normal MSC and osteoblasts. Potential ligands included transforming growth factor β1 (TGFB1) from osteoblasts and megakaryocytes. Murine ThPO and JAK2 myelofibrosis models showed co-expression of Nrp2 and Ncam1 in osteolineage cells, while fibrosis-promoting MSC only express Nrp2. In vitro experiments with MC3T3-E1 pre-osteoblasts and analysis of Nrp2/ mouse femurs suggest that Nrp2 is functionally involved in osteogenesis. In summary, NRP2 represents a potential novel druggable target in patients with myelofibrosis.
Insights
Myelofibrosis, a complication of blood cancers, involves abnormal bone marrow cells. Researchers found NRP2 and NCAM1 expression in these cells, suggesting NRP2 as a potential therapeutic target for treating myelofibrosis.
Area of Science:
- Hematology
- Oncology
- Cell Biology
- Biomedical Research
Background:
- Bone marrow fibrosis (MF) is a poor prognostic indicator in myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML).
- MF involves the transformation of bone marrow mesenchymal stromal cells (MSC) into cells that produce excess osteoid and fibrous tissue.
- Understanding the cellular mechanisms driving MF is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the role of NRP2 and NCAM1 in the bone marrow endosteal niche in normal and malignant hematopoiesis.
- To determine if NRP2 and NCAM1 expression correlates with myelofibrosis severity.
- To explore the potential of NRP2 as a therapeutic target for myelofibrosis.
Main Methods:
- Immunohistochemistry on bone marrow samples from 99 patients with MPN, MDS, MPN/MDS overlap syndromes, and AML.
- Single-cell RNA sequencing (scRNAseq) data re-analysis.
- In vitro studies using MC3T3-E1 pre-osteoblasts.
- Analysis of Nrp2 knockout mouse femurs.
- Murine models of myelofibrosis induced by ThPO and JAK2.
Main Results:
- NRP2 and osteolineage marker NCAM1 are expressed in the endosteal niche of normal bone marrow and aberrantly in MPN, MDS, MPN/MDS overlap syndromes, and AML.
- Increased and diffuse expression of NRP2 and NCAM1 in MSC and osteoblasts correlates with higher MF grade in MPN.
- scRNAseq revealed NRP2 expression in endothelial cells and partial co-expression of NRP2 and NCAM1 in normal MSC and osteoblasts.
- Nrp2 plays a functional role in osteogenesis, as suggested by in vitro and in vivo experiments.
Conclusions:
- NRP2 and NCAM1 are aberrantly expressed in the bone marrow niche in myelofibrotic diseases.
- Their expression levels correlate with myelofibrosis severity.
- NRP2 is a potential novel druggable target for patients suffering from myelofibrosis.
