| First Author | Kramer F | Year | 2020 |
| Journal | Haematologica | Volume | 105 |
| Issue | 8 | Pages | 2083-2094 |
| PubMed ID | 31672904 | Mgi Jnum | J:311704 |
| Mgi Id | MGI:6717784 | Doi | 10.3324/haematol.2019.226332 |
| Citation | Kramer F, et al. (2020) Platelet-derived growth factor receptor beta activation and regulation in murine myelofibrosis. Haematologica 105(8):2083-2094 |
| abstractText | There is prevailing evidence to suggest a decisive role for platelet-derived growth factors (PDGF) and their receptors in primary myelofibrosis. While PDGF receptor beta (PDGFRbeta) expression is increased in bone marrow stromal cells of patients correlating with the grade of myelofibrosis, knowledge on the precise role of PDGFRbeta signaling in myelofibrosis is sparse. Using the Gata-1(low) mouse model for myelofibrosis, we applied RNA sequencing, protein expression analyses, multispectral imaging and, as a novel approach in bone marrow tissue, an in situ proximity ligation assay to provide a detailed characterization of PDGFRbeta signaling and regulation during development of myelofibrosis. We observed an increase in PDGFRbeta and PDGF-B protein expression in overt fibrotic bone marrow, along with an increase in PDGFRbeta-PDGF-B interaction, analyzed by proximity ligation assay. However, PDGFRbeta tyrosine phosphorylation levels were not increased. We therefore focused on regulation of PDGFRbeta by protein tyrosine phosphatases as endogenous PDGFRbeta antagonists. Gene expression analyses showed distinct expression dynamics among PDGFRbeta-targeting phosphatases. In particular, we observed enhanced T-cell protein tyrosine phosphatase protein expression and PDGFRbeta-T-cell protein tyrosine phosphatase interaction in early and overt fibrotic bone marrow of Gata-1(low) mice. In vitro, T-cell protein tyrosine phosphatase (Ptpn2) knockdown increased PDGFRbeta phosphorylation at Y(751) and Y(1021), leading to enhanced downstream signaling in fibroblasts. Furthermore, Ptpn2 knockdown cells showed increased growth rates when exposed to low-serum growth medium. Taken together, PDGF signaling is differentially regulated during myelofibrosis. Protein tyrosine phosphatases, which have so far not been examined during disease progression, are novel and hitherto unrecognized components in myelofibrosis. |
