Impaired Expression of Focal Adhesion Kinase in Mesenchymal Stromal Cells from Low-Risk Myelodysplastic Syndrome Patients

Abstract

The pathogenic role of mesenchymal stromal cells (MSCs) in myelodysplastic syndromes (MDS) development and progression has been investigated by numerous studies, yet, it remains controversial in some aspects (1, 2). In the present study, we found distinct features of MSCs from low-risk (LR)-MDS stromal microenvironment as compared to those from healthy subjects. At the molecular level, focal adhesion kinase, a key tyrosine kinase in control of cell proliferation, survival, and adhesion process, was found profoundly suppressed in expression and activation in LR-MDS MSC. At a functional level, LR-MDS MSCs showed impaired growth and clonogenic capacity, which were independent of cellular senescence and apoptosis. The pro-adipogenic differentiation and attenuated osteogenic capacity along with reduced SDF-1 expression could be involved in creating an unfavorable microenvironment for hematopoiesis. In conclusion, our experiments support the theory that the stromal microenvironment is fundamentally altered in LR-MDS, and these preliminary data offer a new perspective on LR-MDS pathophysiology.

Evaluation of bone marrow microenvironment could change how myelodysplastic syndromes are diagnosed and treated

“…In low-risk MDS (LR-MDS), the STRO-1 + and the CD73 + MSCs showed impaired growth and clonogenic capacity, which seem to be independent of cellular senescence and apoptosis, but were correlated with the decreased expression of adhesion markers, especially diminution of CD49e and CD44 molecules (19,88). In addition, the expression of CD166 and CD29 is altered in MDS-derived MSCs, but it is not clear whether these abnormalities are related to the myelodysplastic process (90).…”

“…Preliminary studies with Durvalumab, a PD-L1 inhibitor, showed a reduction of PD-L1 and pSTAT3 expression in patient PBMCs (117). However, the administration of nivolumab (anti-PD1, Opdivo ® , Bristol-Myers Squibb) in single therapy showed no clinical activity (118) The abortion of apoptosis and increased MDS-MSC proliferation through the PAR1-p38 MAPK pathway and pFAK-HSP90-paxillin have been observed in high-risk MDS (76,88). Therefore, FAK inhibitors (e.g., VS-6062) or p38 MAPK inhibitors (e.g., SB203580, which recovers the MDS-MSC apoptosis through MMP-1 restoration) might overcome the progression of an MDS-instructed MSC clone and rescue the normal MSC counterpart.…”

“…In high-risk MDS, it has been observed that the co-localization of the focal adhesion kinase (FAK) with HSP90α/β and paxillin followed by FAK hyper-phosphorylation at site Y937 promotes nuclear sequestration of paxillin with increased MSC proliferation and, indirectly, with impairment of hematopoiesis support (19,87). In addition, during MDS disease progression, the gradual augmentation and activation of FAK expression were observed (87,88). Therefore, the increased expression and activation of FAK could be used to track disease progression.…”

“…In addition, the CD73 + MSCs selected from MDS patients showed a higher propensity toward the pro-adipogenic differentiation and an attenuated osteogenic capacity, along with reduced SDF-1 expression, contributing to an unfavorable microenvironment for hematopoiesis (88). This abnormal differentiation ability correlates with significant FAK downregulation and hypophosphorylation (88). Another explanation for this abnormal differentiation would be the activation of TGF-β-Smad2/3 signaling in MSCs, which induces fibrotic events and adipogenic differentiation via miR-21 (92).…”

“…The abortion of apoptosis and increased MDS-MSC proliferation through the PAR1-p38 MAPK pathway and pFAK-HSP90-paxillin have been observed in high-risk MDS (76,88). Therefore, FAK inhibitors (e.g., VS-6062) or p38 MAPK inhibitors (e.g., SB203580, which recovers the MDS-MSC apoptosis through MMP-1 restoration) might overcome the progression of an MDS-instructed MSC clone and rescue the normal MSC counterpart.…”