Aberrantly expressed Wnt5a in nurse-like cells drives resistance to Venetoclax in chronic lymphocytic leukemia.
Aberrantly expressed Wnt5a in nurse-like cells drives resistance to Venetoclax in chronic lymphocytic leukemia.
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DOI：
10.1038/s41420-022-00884-y
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发表时间：
2022-02-24
影响因子：
7
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Guo Y;Pei H;Lu B;Zhang D;Zhao Y;Wu F;Sun H;Huang J;Li P;Yi C;Zhu C;Pan Y;Wu S;Chen C;Xu X;Chen Y
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of neoplastic B lymphocytes with high levels of Wnt5a in the plasma. Currently, the cell source of Wnt5a remains controversial. The receptor of Wnt5a is ROR1, whose expression is associated with disease progression and resistance to venetoclax, a BCL-2 inhibitor approved for the treatment of CLL. In this study, we found that the levels of Wnt5a in the plasma of CLL patients were positively correlated with absolute monocyte counts, but not lymphocyte counts. We cultured monocyte-derived nurse-like cells (NLCs) from patients with CLL, and detected Wnt5a expressed in NLCs. Flow cytometry and transwell assays showed that the antibody neutralizing Wnt5a inhibited the enhanced survival and migration in CLL cells co-cultured with NLCs. Furthermore, we performed a drug screening with CLL cells cultured with or without NLCs with a library containing 133 FDA-approved oncology drugs by using high-throughput flow cytometry. We observed a significant resistance to venetoclax in CLL cells co-cultured with NLCs. Immunoblot revealed the activation of NF-κB with enhanced expression of MCL-1 and BCL-XL in CLL cells co-cultured with NLCs. Neutralizing Wnt5a or blocking NF-κB pathway significantly decreased the expression of MCL-1 and BCL-XL, which leads to enhanced sensitivity to venetoclax in CLL cells co-cultured with NLCs. In conclusion, our data showed that NLCs could be one of the sources of Wnt5a detected in patients with CLL, and Wnt5a-induced NF-κB activation in the CLL microenvironment results in resistance to venetoclax in CLL cells.
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影响因子：
50.3
作者：
Hayakawa Y;Ariyama H;Stancikova J;Sakitani K;Asfaha S;Renz BW;Dubeykovskaya ZA;Shibata W;Wang H;Westphalen CB;Chen X;Takemoto Y;Kim W;Khurana SS;Tailor Y;Nagar K;Tomita H;Hara A;Sepulveda AR;Setlik W;Gershon MD;Saha S;Ding L;Shen Z;Fox JG;Friedman RA;Konieczny SF;Worthley DL;Korinek V;Wang TC
通讯作者：
Wang TC
影响因子：
20.3
作者：
Ghia, Emanuela M.;Rassenti, Laura Z.;Kipps, Thomas J.
通讯作者：
Kipps, Thomas J.
影响因子：
20.3
作者：
Chen, Yun;Chen, Liguang;Kipps, Thomas J.
通讯作者：
Kipps, Thomas J.
DOI：
10.1073/pnas.0712148105
发表时间：
2008-02-26
影响因子：
11.1
作者：
Fukuda, Tetsuya;Chen, Liguang;Kipps, Thomas J.
通讯作者：
Kipps, Thomas J.
影响因子：
11.4
作者：
Hasan MK;Ghia EM;Rassenti LZ;Widhopf GF 2nd;Kipps TJ
通讯作者：
Kipps TJ