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

Abstract

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.

Tipping the balance: toward rational combination therapies to overcome venetoclax resistance in mantle cell lymphoma

“…Interestingly, T cells also play a role by CD40-mediated induction of IL-32β, which in turn instructs the TAMS to secrete BAFF [ 38 , 39 ]. This is in concordance with the more established role of TAMs in CLL, where TAMs induce lymphoma survival via secretion of a proliferation-inducing ligand (APRIL), BAFF, CXCL12 and -13, and Wnt5a, and via stimulation of the BCR and CD38 [ 40 , 41 ]. These stimuli activate NF-κB, AKT and ERK, resulting in upregulation of anti-apoptotic proteins, such as BCL-2, BCL-X L , and BFL-1 and downregulation of BAD (Fig.…”

“…2B ), combining venetoclax with inhibition of NF-κB signaling might also be a promising approach to increase the efficacy of venetoclax in patients. Indeed, prevention of IκB degradation in MCL cell lines and primary samples downregulated BCL-X L and in some cases also MCL-1 or BCL-2 [ 34 , 41 , 73 ]. Furthermore, inhibition of the non-canonical NF-κB pathway using an NF-κB inducing kinase (NIK) inhibitor in MCL and CLL reduced BCL-X L levels and led to increased vulnerability to venetoclax [ 38 , 74 ].…”

The strange case of nurse cells: Dr. Jekyll or Mr. Hyde?

“…NLCs were also described for mediating resistance to venetoclax, the Bcl2 antagonist and Bcl2 being highly expressed in CLL cells, through an aberrant expression of Wnt5a. Neutralizing Wnt5a significantly inhibited NLC-induced survival, migration and the corresponding cell signaling in CLL cells, indicating novel mechanisms for venatoclax resistance as well as potential therapeutic options to circumvent this resistance [81].…”

How receptor tyrosine kinase‐like orphan receptor 1 meets its partners in chronic lymphocytic leukemia

“…Cirmtuzumab potentiates venetoclax cytotoxicity for high-level ROR1 CLL cells suggesting synergistic ROR1 and BCL2 targeting potential. 78 Wnt5a neutralization counters this signaling, indicating its role in NLCs-CLL cell interaction. These findings reveal resistance mechanisms and suggest Wnt5a as a potential therapeutic target.…”