title: Sonic hedgehog produced by bone marrow-derived mesenchymal stromal cells supports cell survival in myelodysplastic syndrome.
abstract: The role of marrow microenvironment in the pathogenesis of myelodysplastic syndrome (MDS) remains controversial. Therefore, we studied the influence of bone marrow-derived mesenchymal stromal cells (BMSCs) from patients with different risk types of MDS on the survival of the MDS cell lines SKM-1 and MUTZ-1. We first demonstrated that the expression of Sonic hedgehog (Shh), smoothened (Smo), and glioma-associated oncogene homolog 1 (Gli1) was increased in MDS patients (n = 23); the increase in expression was positively correlated with the presence of high-risk factors. The Shh signaling inhibitor, cyclopamine, inhibited high-risk MDS BMSC-induced survival of SKM-1 and MUTZ-1 cells, suggesting a role for Shh signaling in MDS cell survival. Furthermore, cyclopamine-mediated inhibition of Shh signaling in SKM-1 and MUTZ-1 cells resulted in decreased DNMT1 expression and cell survival; however, exogenous Shh peptide had the opposite effect, suggesting that Shh signaling could regulate the expression of DNMT1, thereby modulating cell survival in MDS. In addition, the apoptosis of SKM-1 and MUTZ-1 cell increased significantly when cultured with cyclopamine and a demethylation agent, 5-Aza-2'-deoxycytidine. These findings suggest that Shh signaling from BMSCs is important in the pathogenesis of MDS and could play a role in disease progression by modulating methylation.
authors: Department of Hematology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai 200080, China.
authors: Jixue
authors: J
authors: Zou
authors: Experimental Research Center, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai 200080, China.
authors: Yan
authors: Y
authors: Hong
authors: Department of Hematology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai 200080, China.
authors: Yin
authors: Y
authors: Tong
authors: Department of Hematology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai 200080, China.
authors: Ju
authors: J
authors: Wei
authors: Department of Hematology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai 200080, China.
authors: Youwen
authors: Y
authors: Qin
authors: Department of Hematology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai 200080, China.
authors: Shan
authors: S
authors: Shao
authors: Department of Hematology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai 200080, China.
authors: Chun
authors: C
authors: Wang
authors: Department of Hematology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai 200080, China.
authors: Kun
authors: K
authors: Zhou