The Role Played by Wnt/β-Catenin Signaling Pathway in Acute Lymphoblastic Leukemia

Abstract

Acute lymphoblastic leukemia (ALL) is an aggressive hematologic neoplastic disorder that arises from the clonal expansion of transformed T-cell or B-cell precursors. Thanks to progress in chemotherapy protocols, ALL outcome has significantly improved. However, drug-resistance remains an unresolved issue in the treatment of ALL and toxic effects limit dose escalation of current chemotherapeutics. Therefore, the identification of novel targeted therapies to support conventional chemotherapy is required. The Wnt/β-catenin pathway is a conserved signaling axis involved in several physiological processes such as development, differentiation, and adult tissue homeostasis. As a result, deregulation of this cascade is closely related to initiation and progression of various types of cancers, including hematological malignancies. In particular, deregulation of this signaling network is involved in the transformation of healthy HSCs in leukemic stem cells (LSCs), as well as cancer cell multi-drug-resistance. This review highlights the recent findings on the role of Wnt/β-catenin in hematopoietic malignancies and provides information on the current status of Wnt/β-catenin inhibitors with respect to their therapeutic potential in the treatment of ALL.

Keywords: Wnt/β-catenin; acute lymphoblastic leukemia; hematopoietic stem cells; leukemic stem cells; signaling pathway; targeted therapy.

Figure 1

Schematic representation of the Wnt/β-catenin signaling pathway, which is inactive in the absence of Wnt ligands (OFF) and active upon binding of Wnt ligands (ON). See text for details of pathway activation. Arrows show activation while T-bars show inhibition.

Figure 2

Schematic representation of the regulation of the Wnt/β-catenin signaling pathway when it is inactive (OFF) and when it is active (ON). OFF: ZNRF3 and RNF43 are transmembrane molecules that downregulate Wnt/β-catenin signaling. They promote the ubiquitination (UB) and lysosomal degradation of Fzd and LRP5/6. Secreted SFRP, APCDD1, and WIF can directly bind Fzd to prevent activation of receptors. Other Wnt antagonists, Dkk1 and Wise, inhibit by binding to the co-receptors LRP5/6. GRG/TLE, CtBP1, and HDAC negatively control Wnt/β-catenin pathway binding to TCF. ON: The Wnt agonists R-spondins interact on the cell surface with members of the LGR4/5 family to enhance Wnt signaling. Binding of R-spondin to ZNRF3/RNF43 inhibits ZNRF3, which enhances the Wnt/β-catenin pathway activity. Norrin acts by interacting with Fzd4 and requiring LRP5/6 for its activation. Arrows show activation while T-bars show inhibition.

Figure 3

Role of Wnt/β-catenin signaling pathway in hematopoiesis and leukemogenesis. Wnt/β-catenin axis is differentially regulated during hematopoiesis. When the pathway is inhibited, correct hematopoiesis is compromised whereas, when slightly activated, there is an increase of hematological stem cell (HSC) clonogenicity and myeloid development. Intermediate-high levels lead to T-cell development. In addition, very high Wnt/β-catenin activation may lead to impaired hematopoiesis and leukemia development.