The Role of Wnt/β -Catenin Signaling in Normal and Malignant Hematopoiesis, Hemostasis
The Wnt/β-catenin signaling plays indispensable roles in embryonic development and adult homeostasis. Through diverse mechanisms which are partially defined, abnormal activation of β-catenin occurs frequently in neoplastic disease. A critical function for Wnt/β-catenin in solid tumors, in particular colorectal cancer, has been well characterized. Increasing evidence indicates that this pathway is also deregulated in hematological malignancies. In acute myeloid leukemia, enhanced β-catenin levels are observed in a large proportion of patients, and correlates with increased blast clonogenicity and poor outcome. Similarly, in chronic myeloid leukemia (CML), Wnt/β-catenin activation is observed in advanced disease, and inhibition of β-catenin in vivo potentiates the effect of tyrosine kinase inhibitors in mouse models of CML. While studies suggest that β-catenin may be dispensable for steady-state maintenance of adult hematopoietic stem cells, a critical function for this pathway in regulation of specialized leukemic stem cells (LSC) is emerging. Here we review the currently understood mechanisms and roles of β-catenin in hematological malignancies, and describe the evidence outlining the contribution of β-catenin activation in mediating the self-renewal and drug-resistant properties of LSC. In addition, given the implication of LSC in disease relapse, we discuss current approaches and limitations of targeting the Wnt/β-catenin axis in the clinic.