4.6 Article

Aberrantly expressed Wnt5a in nurse-like cells drives resistance to Venetoclax in chronic lymphocytic leukemia

Journal

CELL DEATH DISCOVERY
Volume 8, Issue 1, Pages -

Publisher

SPRINGERNATURE
DOI: 10.1038/s41420-022-00884-y

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Funding

  1. Guangdong Provincial Key Laboratory of Digestive Cancer Research [2021B1212040006]
  2. Natural Science Foundation of Guangdong Province [2014A0303013398]
  3. National Natural Science Foundation of China (NSFC) [82000150]
  4. Medical Research Programs of Guangdong Province [A2020442]
  5. Shenzhen Science and Technology Innovation Commission [JCY20180307150614412, JCYJ20190814164601648, JCYJ20190812093601675]
  6. Sanming Project of Medicine in Shenzhen [SZSM201911004]

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Plasma levels of Wnt5a in chronic lymphocytic leukemia (CLL) patients are positively correlated with absolute monocyte counts, but not lymphocyte counts. Nurse-like cells (NLCs) derived from CLL patients express Wnt5a. Wnt5a-induced NF-kappa B activation in the CLL microenvironment results in resistance to venetoclax in CLL cells.
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-kappa B with enhanced expression of MCL-1 and BCL-XL in CLL cells co-cultured with NLCs. Neutralizing Wnt5a or blocking NF-kappa B 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-kappa B activation in the CLL microenvironment results in resistance to venetoclax in CLL cells.

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