Overexpression of the TGF-β target CCN2 in megakaryocytes: a common feature of MDS with mutated SF3B1

Abstract Cellular Communication Network Factor 2 (CCN2) is known to support hematopoietic stem cells and its altered expression is linked to various hematologic malignancies. As a target of canonical Transforming growth factor (TGF)-β signaling, its overexpression will mediate downstream effects of hyperactivation of this pathway, which is frequently observed in myelodysplastic syndromes (MDS). Therefore, we analyzed CCN2 protein expression in bone marrow biopsies from 50 MDS patients and 20 controls, and correlated the findings with clinicopathological features. CCN2 overexpression in megakaryocytes was found in 32% of MDS patients. Among all analyzed factors, the MDS subtype ‘MDS with mutated SF3B1 ’ showed the strongest correlation with CCN2 overexpression ( p < 0.001). SF3B1 mutations alone were also associated with CCN2 overexpression, though less strongly ( p = 0.024). Moreover, spliceosome gene mutations overall were significantly more frequent in CCN2-overexpressing cases ( p = 0.042). Activation of TGF-β signaling is considered as possible mechanism for CCN2 overexpression, but functional studies are required to substantiate this hypothesis. An inverse association was observed between CCN2 overexpression and the presence of mutations in RUNX1 and/or ASXL1 ( p = 0.013), which may reflect a suppressive effect of these mutations on canonical TGF-β signaling activity. In aggregate, these findings may contribute to a better understanding of disease pathophysiology and help elucidate the role of potentially clinically relevant TGF-β signaling. This is particularly significant given the clinical use of agents targeting TGF-β-signaling such as luspatercept, as well as the emergence of several CCN2-targeting therapies currently undergoing clinical or preclinical evaluation with promising results.