Understanding the Wnt Signaling Pathway in Acute Myeloid Leukemia Stem Cells: A Feasible Key against Relapses

Abstract

Wnt signaling is a highly conserved pathway in evolution which controls important processes such as cell proliferation, differentiation and migration, both in the embryo and in the adult. Dysregulation of this pathway can favor the development of different types of cancer, such as acute myeloid leukemia and other hematological malignancies. Overactivation of this pathway may promote the transformation of pre-leukemic stem cells into acute myeloid leukemia stem cells, as well as the maintenance of their quiescent state, which confers them with self-renewal and chemoresistance capacity, favoring relapse of the disease. Although this pathway participates in the regulation of normal hematopoiesis, its requirements seem to be greater in the leukemic stem cell population. In this review, we explore the possible therapeutic targeting of Wnt to eradicate the LSCs of AML.

Keywords: AML; HSCs; Hedgehog; LSCs; Notch; hematopoiesis; quiescence; β-catenin.

Figure 1

Canonical Wnt pathway. (A) In the canonical Wnt/β-catenin pathway, binding of the Wnt ligand to the FZD receptor and co-receptor LRP5/6 promotes phosphorylation of LRP5/6 by CKIα and GSK3β kinases and polymerization of the DVL protein. Therefore, the destroyer complex is inactivated (Axin, APC, CKIα and GSK3β) and the β-catenin protein is accumulated in the cytosol. The β-catenin translocates to the nucleus and interacts with the TCF/LEF complex, promoting the recruitment of transcriptional co-activators (CBP/p300, BRG1, BCL9 and Pygo), inducing the expression of target genes. (B) In the absence of the Wnt ligand, the destructor complex phosphorylates and induces ubiquitination of β-catenin by βTrCP for its degradation in the proteosome. The absence of nuclear β-catenin favors the recruitment of HDACs by the TCF/LEF and Groucho/TLE repressor complexes, thus inhibiting the expression of target genes. Non-canonical Wnt pathway. Non-canonical Wnt ligands can activate other non-canonical β-catenin-independent signaling pathways, such as the Wnt/PCP and Wnt/Ca²⁺. In the Wnt/Ca²⁺ pathway, the Wnt ligand binds to FZD and ROR1/2 and promotes PLC activation via G proteins in a DVL-dependent way. PLC catalyzes the formation of IP3 and DAG, which results in an increase of Ca²⁺ in the cytosol and activation of kinases such as PKC, Calcineurin and CAMKII. These kinases can modify the cytoskeleton through the small GTPase CDC42 and/or regulate transcription of target genes through NFAT, NFκβ and CREB, among others. In the Wnt/PCP pathway, binding of the Wnt ligand to the FZD receptor and co-receptors, such as ROR1/2, favors the activation of small GTPases of the Rho family (RHOA, RAC) by DVL. RHOA and RAC activate JNK kinases and ROCK kinases, which are involved in the reorganization of the cytoskeleton and/or activation of gene expression via Jun/ATF2, among others. Dashed arrows indicate an indirect activation.

Figure 2

Studies related to the role of the Wnt/β-catenin signaling pathway in Acute Myeloid Leukemia. (A) In AML, overexpression of ligands, receptors or transcription factors of the Wnt pathway, such as WNT1, WNT2B, WNT10B, FZD4 and LEF-1, entails an antiapoptotic effect. (B) Silencing by promoter hypermethylation of Wnt regulatory genes, such as SFRPs, DKK1, RUNX3, SOX17 or WIF1, can activate the pathway. Deletion of Gsk3β also activates the Wnt pathway. These actions favor aggressive development of AML. (C) The inhibition of Foxm1 in KMT2A-rearranged AML LSCs favors the quiescent state due to the activation of the Wnt signaling pathway.