To β or Not to β: How Important Is β-Catenin Dependent and Independent WNT Signaling in CLL?

SIMPLE SUMMARY: This review aims to present the current state of WNT signaling in chronic lymphocytic leukemia. First, we briefly summarize WNT pathways in physiological conditions and cancer. Then, we focus on WNT pathways in CLL with an emphasis on ROR1. The problem of limited data on canonical WNT signaling in CLL is also highlighted. In conclusion, we suggest that further research should focus on understanding the role of β-catenin signaling in CLL. ABSTRACT: WNT pathways play an important role in cancer development and progression, but WNT pathways can also inhibit growth in melanoma, prostate, and ovarian cancers. Chronic lymphocytic leukemia (CLL) is known for its overexpression of several WNT ligands and receptors. Canonical WNT signaling is β-catenin-dependent, whereas non-canonical WNT signaling is β-catenin-independent. Research on WNT in CLL focuses mainly on non-canonical signaling due to the high expression of the WNT-5a receptor ROR1. However, it was also shown that mutations in canonical WNT pathway genes can lead to WNT activation in CLL. The focus of this review is β-catenin-independent signaling and β-catenin-dependent signaling within CLL cells and the role of WNT in the leukemic microenvironment. The major role of WNT pathways in CLL pathogenesis also makes WNT a possible therapeutic target, directly or in combination with other drugs.