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Busy signal: platelet-derived growth factor activation in myelofibrosis
Anna E. Marneth1 and Ann Mullally1,2,3
1Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston; 2Dana-Farber Cancer Institute, Harvard Medical School, Boston and 3Broad Institute, Cambridge, MA, USA.
E-mail: ANN MULLALLY - amullally@partners.org doi:10.3324/haematol.2020.253708
The pathogenesis of myelofibrosis, a bone marrow (BM) disorder characterized by megakaryocytic hyperplasia and the deposition of extracellular matrix components such as reticulin, remains incompletely understood.
Using a mouse model of myelofibrosis (i.e. Gata-1low mice), Kramer et al.1 sought to identify key signaling mole- cules that play a role in early myelofibrosis development. GATA-1 is a transcription factor that is key to megakary- ocyte development, and its downregulation results in expansion and abnormal maturation of megakaryocytes.2 Importantly, low GATA-1 expression has been demonstrat- ed in patients with myelofibrosis,3 and GATA-1 mutations are found in megakaryocytic leukemias.2
New key findings
Unlike several widely used myelofibrosis mouse mod- els that rely on BM transplantation to engender fibrosis, primary Gata-1low mice gradually develop myelofibrosis spontaneously.4 Due to its slow progression, this model allows for analysis at prefibrotic (5 months), early fibrotic (10 months), and overtly fibrotic (15 months) stages. A strength of the study by Kramer et al. is the application of an unbiased approach (i.e. RNA sequencing) to interro- gate the changes that occur in receptor tyrosine kinase pathways during the development of myelofibrosis. Using bulk RNA sequencing on unfractionated BM (including stromal cells), the authors identified the platelet-derived growth factor (PDGF) pathway as signif- icantly up-regulated in early fibrotic Gata-1low mice com- pared to wild-type mice. Additionally, the authors ana- lyzed protein expression of PDGF receptors and ligands
on BM sections at the three aforementioned time points; this allowed them to study the PDGF pathway in a spa- tio-temporal manner.
In addition to demonstrating increased transcript expres- sion of PDGF receptor a (Pdgfra) and Pdgfrb, as well as the ligand Pdgfb, in fibrotic Gata-1low mice, the authors employed a novel technique called in situ proximity liga- tion assay to determine protein localization. They found that the receptor PDGFRb and ligand PDGF-B are in close proximity in the setting of overtly fibrotic BM, suggesting binding of the ligand to the receptor and increased PDGF- B signaling. Furthermore, their data suggest that the most important cell types involved in PDGF signaling are megakaryocytes, which express PDGFRa and secrete the ligand PDGF-B, and spindle-shaped stromal cells which express PDGFRb (Figure 1).
Despite these findings, Kramer et al. did not detect increased PDGFRb tyrosine phosphorylation, a marker of receptor activation. They suggest that the phosphatase TC-PTP (PTPN2) may play a role in dephosphorylation of PDGFRb and show that TC-PTP is in close proximity to PDGFRb in fibrotic Gata-1low mice. There are two main potential explanations for these findings. Either: (i) PDGF receptor activation is transient and rapidly down-regulat- ed; or (ii) PDGF receptor activation is rapidly reset by phos- phatases such as TC-PTP after ligand binding. Rapid downregulation would call into question the importance of the PDGF pathway in myelofibrosis, while a rapid reset may increase signaling in the presence of ligand and poten- tially contribute to the development of myelofibrosis. Further investigation of PDGF signaling in human myelofi- brosis will be required to fully resolve this question.
haematologica | 2020; 105(8)