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

Francesca Chiarini,Camilla Evangelisti,Alberto M Martelli,Francesca Paganelli

doi:10.3390/ijms21031098

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.

Highlights

Acute lymphoblastic leukemia (ALL) is an aggressive hematological disorder that can originate from either B-lineage (B-ALL) or T-lineage (T-ALL) lymphoid precursors and is characterized by a marked heterogeneity at both molecular and clinical levels.B-ALL is the most frequent neoplasia in childhood, which represents 80% of pediatric ALL [1]
T-ALL has a worse prognosis compared to B-ALL and, especially in adults, drug-resistance remains an unresolved issue in the treatment of T-ALL and dose escalation of current chemotherapeutics is limited by side effects
Nygren et al [93] suggested that the effects of Wnt/β-catenin pathway in B-ALL development could be related to different anomalies such as genetic aberrations, including translocations, or could be due to interactions with other non-canonical signaling pathways, or to β-catenin localization

Summary

Introduction

Acute lymphoblastic leukemia (ALL) is an aggressive hematological disorder that can originate from either B-lineage (B-ALL) or T-lineage (T-ALL) lymphoid precursors and is characterized by a marked heterogeneity at both molecular and clinical levels. Upregulated β-catenin and Hif1α may sustain LSCs, while deletion of these proteins strongly decreased LSCs frequency, without interfering with the growth of bulk cancer cells [86] This functional dependency of LSCs may have an important clinical impact on the treatment of T-ALL, as it suggests that inhibition of the Wnt/β-catenin signaling pathway could be a useful approach to treat leukemia, especially for refractory T-ALL patients [86]. Activation of the Wnt/β-catenin network may be a general phenomenon that characterizes B-ALL, acting as a mean for the microenvironment to sustain the survival of the LSCs. Nygren et al [93] suggested that the effects of Wnt/β-catenin pathway in B-ALL development could be related to different anomalies such as genetic aberrations, including translocations, or could be due to interactions with other non-canonical signaling pathways, or to β-catenin localization. Different ways to inhibit Wnt/β-catenin signaling are currently under investigation for acute leukemias (see Table 1)

Clinical Trials

Findings

Conclusions and Perspectives