Wnt5a enhances proliferation of chronic lymphocytic leukemia and ERK1/2 phosphorylation via a ROR1/DOCK2-dependent mechanism

Hasan, Kamrul; Ghia, Emanuela M.; Rassenti, Laura Z.; Widhopf, George F.; Kipps, Thomas J.

doi:10.1038/s41375-020-01055-7

Cited by 27 publications

(28 citation statements)

References 50 publications

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“…51,52 Also, other factors independent of the TNFR family of proteins may play a role in the activation of NF-kB, as noted recently for Wnt5a-ROR1 via a mechanism that functions independent of the TNFR family of receptors. [53][54][55][56] Altogether these and our data support a model by which CD4 1 T cells are essential for CLL development and progression in TCL1 mice, through mechanisms that are independent of the CD40/ CD40L axis. More studies are warranted to further define which membrane-bound or soluble factor is directly responsible for this T-cell-mediated effect, because this might have relevant implications in the future design of novel treatments for patients with CLL.…”

Section: Discussionsupporting

confidence: 83%

CD4+ T cells sustain aggressive chronic lymphocytic leukemia in Eμ-TCL1 mice through a CD40L-independent mechanism

Grioni¹,

Brevi²,

Cattaneo³

et al. 2021

Blood Advances

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Chronic lymphocytic leukemia (CLL) is caused by the progressive accumulation of mature CD5+ B cells in secondary lymphoid organs. In vitro data suggest that CD4+ T lymphocytes also sustain survival and proliferation of CLL clones through CD40L/CD40 interactions. In vivo data in animal models are conflicting. To clarify this clinically relevant biological issue, we generated genetically modified Eμ-TCL1 mice lacking CD4+ T cells (TCL1+/+AB0), CD40 (TCL1+/+CD40−/−), or CD8+ T cells (TCL1+/+TAP−/−), and we monitored the appearance and progression of a disease that mimics aggressive human CLL by flow cytometry and immunohistochemical analyses. Findings were confirmed by adoptive transfer of leukemic cells into mice lacking CD4+ T cells or CD40L or mice treated with antibodies depleting CD4 T cells or blocking CD40L/CD40 interactions. CLL clones did not proliferate in mice lacking or depleted of CD4+ T cells, thus confirming that CD4+ T cells are essential for CLL development. By contrast, CD8+ T cells exerted an antitumor activity, as indicated by the accelerated disease progression in TCL1+/+TAP−/− mice. Antigen specificity of CD4+ T cells was marginal for CLL development, because CLL clones efficiently proliferated in transgenic mice whose CD4 T cells had a T-cell receptor with CLL-unrelated specificities. Leukemic clones also proliferated when transferred into wild-type mice treated with monoclonal antibodies blocking CD40 or into CD40L−/− mice, and TCL1+/+CD40−/− mice developed frank CLL. Our data demonstrate that CD8+ T cells restrain CLL progression, whereas CD4+ T cells support the growth of leukemic clones in TCL1 mice through CD40-independent and apparently noncognate mechanisms.

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Section: Discussionsupporting

confidence: 83%

CD4+ T cells sustain aggressive chronic lymphocytic leukemia in Eμ-TCL1 mice through a CD40L-independent mechanism

Grioni¹,

Brevi²,

Cattaneo³

et al. 2021

Blood Advances

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“…3B ). We also examined phosphorylation of ERK, HS1, and p65 in CLL cells co-cultured with NLCs, which account for Wnt5a-induced survival and migration of CLL cells according to our previous studies [ 13 , 23 , 30 ]. We found that CLL cells co-cultured with NLCs, but not CLL cells cultured alone, had high-level of phosphorylated ERK, HS1, and p65.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2022

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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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“…Other pathways activated by WNT/ROR signaling comprise MAPK/ERK [ 18 , 88 , 168 ], STAT3 [ 105 , 169 ], or NF-κB [ 170 ]. However, which specific ROR functions are mediated by the crosstalk with these pathways is not yet fully understood.…”

Section: Wnt/ror Signaling At a Glancementioning

confidence: 99%

The WNT/ROR Pathway in Cancer: From Signaling to Therapeutic Intervention

Menck

Heinrichs

Baden

et al. 2021

Cells

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The WNT pathway is one of the major signaling cascades frequently deregulated in human cancer. While research had initially focused on signal transduction centered on β-catenin as a key effector activating a pro-tumorigenic transcriptional response, nowadays it is known that WNT ligands can also induce a multitude of β-catenin-independent cellular pathways. Traditionally, these comprise WNT/planar cell polarity (PCP) and WNT/Ca2+ signaling. In addition, signaling via the receptor tyrosine kinase-like orphan receptors (RORs) has gained increasing attention in cancer research due to their overexpression in a multitude of tumor entities. Active WNT/ROR signaling has been linked to processes driving tumor development and progression, such as cell proliferation, survival, invasion, or therapy resistance. In adult tissue, the RORs are largely absent, which has spiked the interest in them for targeted cancer therapy. Promising results in preclinical and initial clinical studies are beginning to unravel the great potential of such treatment approaches. In this review, we summarize seminal findings on the structure and expression of the RORs in cancer, their downstream signaling, and its output in regard to tumor cell function. Furthermore, we present the current clinical anti-ROR treatment strategies and discuss the state-of-the-art, as well as the challenges of the different approaches.

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Wnt5a enhances proliferation of chronic lymphocytic leukemia and ERK1/2 phosphorylation via a ROR1/DOCK2-dependent mechanism

Cited by 27 publications

References 50 publications

CD4+ T cells sustain aggressive chronic lymphocytic leukemia in Eμ-TCL1 mice through a CD40L-independent mechanism

CD4+ T cells sustain aggressive chronic lymphocytic leukemia in Eμ-TCL1 mice through a CD40L-independent mechanism

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

The WNT/ROR Pathway in Cancer: From Signaling to Therapeutic Intervention

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