Canonical WNT Signaling Pathway is Altered in Mesenchymal Stromal Cells From Acute Myeloid Leukemia Patients And Is Implicated in BMP4 Down-Regulation
Canonical WNT Signaling Pathway is Altered in Mesenchymal Stromal Cells From Acute Myeloid Leukemia Patients And Is Implicated in BMP4 Down-Regulation
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DOI：
10.1016/j.tranon.2019.01.003
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发表时间：
2019-04-01
影响因子：
5
通讯作者：
Binato, Renate
中科院分区：
文献类型：
--
作者：
Azevedo, Pedro L.;Olivetra, Nathalia C. A.;Binato, Renate
间充质基质细胞（Mesenchymal stromal cells，hMSCs）是骨髓微环境（bone marrow microenvironment，BMM）的重要组成部分。已经提出了来自急性髓性白血病患者的hMSC（hMSC-AML）中的分子特征，其中BMP 4减少并且可以通过WNT信号通路调节。因此，本研究的目的是验证WNT信号通路是否可以调控hMSCs中的BMP 4基因。结果显示，hMSC-AML和来自健康供体的hMSC之间的WNT经典途径中的差异表达基因和实时定量测定证实了这些发现。此外，在hMSC-AML中，主要的WNT经典途径调节剂，如LEF-1，B-catenin和B-catenin/TCF-LEF调节复合物在细胞核中减少。该结果与功能测定一起表明，在hMSC-AML中，WNT信号通路对BMP 4表达的诱导减少。总体而言，WNT经典途径能够调节hMSC-AML中的BMP 4基因，并且其降低的活化也可能导致hMSC-AML中BMP 4的表达降低。由于BMM的重要作用，通过WNT经典途径改变BMP 4表达可能是白血病发生的潜在机制。
Mesenchymal stromal cells (hMSCs) are key components of the bone marrow microenvironment (BMM). A molecular signature in hMSCs from Acute myeloid leukemia patients (hMSC-AML) has been proposed where BMP4 is decreased and could be regulated by WNT signaling pathway. Therefore, the aim of this work was to verify whether the WNT signaling pathway can regulate the BMP4 gene in hMSCs. The results showed differentially expressed genes in the WNT canonical pathway between hMSC-AML and hMSCs from healthy donors and a real-time quantitative assay corroborated with these findings. Moreover, the main WNT canonical pathway regulators were decreased in hMSC-AML, such as LEF-1, B-catenin and the B-catenin/TCF-LEF regulatory complex in the nucleus. This result, together with functional assays, suggests that the induction of BMP4 expression by the WNT signaling pathway is decreased in hMSC-AML. Overall, the WNT canonical pathway is able to regulate the BMP4 gene in hMSC-AML and its reduced activation could also lead to the lower expression of BMP4 in hMSC-AML. Due to the important role of the BMM, changes in BMP4 expression through the WNT canonical pathway may be a potential mechanism of leukemogenesis.