Wnt/β-Catenin/LEF-1 Signaling in Chronic Lymphocytic Leukemia (CLL): A Target for Current and Potential Therapeutic Options

Abstract

There is a growing body of evidence that Wnt signaling, which is already known to play a critical role in various types of cancer, also has a vital function in B cell neoplasias, particularly in chronic lymphocytic leukemia (CLL). It is known that Wnt proteins are overexpressed in primary CLL cells and several physiological inhibitors are partly inactivated in this disease. Furthermore, β-catenin is upregulated upon Wnt stimulation and cooperates with the transcription factor lymphoid enhancer binding factor-1 (LEF-1). LEF-1 is excessively overexpressed in CLL cells by more than 3,000-fold compared to normal B cells. Moreover, LEF-1 could be identified as an important regulator of pathophysiologically relevant genes in CLL, and several Wnt/β-catenin signaling components substantially influence CLL cell survival. In this review we summarize the current state of knowledge about Wnt/β-catenin/LEF-1 signaling in CLL. Following a short overview of current treatment concepts in CLL, we briefly describe Wnt signaling in human cancers. We then discuss recent progress in understanding regulation of the Wnt/β-catenin/LEF-1 signaling pathway in this disease. Based on the present scientific evidence we highlight which components of this important signaling pathway could serve as therapeutic targets in CLL. We then present previous results gained from experimental approaches to target different parts of the Wnt/β-catenin/LEF-1 cascade. Together with potentially promising approaches we also critically reflect on the kind of difficulties and problems that may arise using such strategies.

β-Catenin induces T-cell transformation by promoting genomic instability

“…In normal development Wnt activity is shortlived and expression of Wnt target genes oscillates, suggesting that Wnt activity is controlled by inherent negative feedback loops (8). Uncontrolled activation of the central effector of Wnt signaling, β-catenin, has been causatively linked to genome instability in multiple cancers, including hematopoietic malignancies (9)(10)(11)(12). However, how uncontrolled β-catenin promotes genomic instability in these malignancies is unknown.…”

Genetic lesions associated with chronic lymphocytic leukemia chemo-refractoriness

“…42 Moreover, b-catenin, as well as LEF1/b-catenin inhibitors, prolonged CLL cell survival, indicating that the Wnt pathway could play a role in CLL pathogenesis. [40][41][42][43] Indeed, other genes belonging to this pathway were mutated in our discovery panel (PTPRU, MED12, and INVS) in a mutual exclusive fashion. [44][45][46] Notably, MED12 has been recently recognized as a driver in CLL by Landau et al, 47 and in this context, a pivotal role in CLL pathogenesis has been ascribed to the Wnt pathway.…”

“…39 The role of the Wnt pathway in CLL has been explored in several papers. [40][41][42][43] Gene expression analysis showed that several members of the Wnt family, as well as the transcription factor LEF1, are overexpressed in CLL cells compared with peripheral blood B cells from healthy donors. 40,41 On the other hand, it was reported that Wnt/b-catenin inhibitor genes were hypermethilated.…”

Aberrant Hypermethylation of APC Tumor Supressor Gene in Acute Leukemia Patients.

“…1,2 Most of the studies reported that up-regulation of B-CATENIN causes the stimulation of WNT pathway and overexpressed WNT proteins contribute to the pathogenesis of hematologic malignancies like acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and T cell acute lymphoblastic leukemia. [3][4][5] APC gene is a multi-domain protein and inactivating mutations or methylations lead to deregulated WNT signaling which has been firstly implicated in colorectal tumor evolution. 6,7 APC gene is the negative regulator of the WNT pathway, has been methylated in solid tumors especially colon prostate, breast cancers, multiple myeloma and acute leukemia.…”