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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.

SUBMITTER: Lainez-Gonzalez D

PROVIDER: S-EPMC10215262 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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

Láinez-González Daniel D Alonso-Aguado Ana Belén AB Alonso-Dominguez Juan Manuel JM

Biology 20230505 5

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 o ...[more]

PMID: 37237497

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Project description:BackgroundAcute myeloid leukemia (AML) is initiated and maintained by a unique, small subset of leukemia stem cells (LSCs). LSCs are characterized by unrestricted self-renewal and contribute to the malignancy of leukemia. Aberrant protein fucosylation is associated with AML progression. However, it is still less understood that the miR-29b/Sp1/FUT4 crosstalk involved in the fucosylation-mediated LSCs malignancy in AML.MethodsAML cell lines were sorted by magnetic microbeads to obtain the CD34 + CD38- sub-population. The key biomarkers for LSCs were identified by flow cytometry. Fucosyltransferase genes were screened by qRT-PCR, and FUT4 was focused. Effect of FUT4 on LSCs malignancy was determined by CCK8 assay, sphere formation assay, immunofluorescence staining, apoptosis and in vivo xenografts experiments. The linkage of FUT4 promoter and Sp1 was confirmed by dual-luciferase reporter gene assay. ChIP-PCR assay was used to show the directly binding of Sp1 and FUT4 promoter. Activity of Wnt//β-catenin pathway was determined by western blot. Overall survival curves were diagrammed by Kaplan-Meier analysis.ResultsHere, the expressional profiles of 11 fucosyltransferase genes were different comparing LSCs and non-LSCs of KG-1a and MOLM13 cells, whereas CD34 + CD38- cells exhibited higher expression of FUT4. Functionally, alteration of FUT4 in CD34 + CD38- cells modulated LSCs malignant behaviors both in vitro and in vivo. Transcriptional inhibitor actinomycin D (Act D) or translational inhibitor cycloheximide (CHX) prevented LSCs progression, and Sp1 was identified as the efficient regulator of FUT4 transcription. Moreover, miR-29b directly affected the binding of Sp1 and FUT4 promoter region, which further mediated LSCs proliferation, apoptosis and drug-resistance through fucosylated-CD44 via activation of Wnt/β-catenin pathway. Clinically, Sp1 and FUT4 were up-regulated and positively correlated with poor overall survival of AML patients.ConclusionThese data indicated that miR-29b/Sp1/FUT4 axis promoted the malignant behaviors of LSCs by regulating fucosylated CD44 via Wnt/β-catenin pathway. Identifying LSCs surface markers and targeting LSCs were important for the development of potential therapies in AML.

Project description:The acute myeloid leukemia (AML)-associated translocation products AML1-ETO, PML-retinoic acid receptor alpha (RARalpha), and PLZF-RARalpha encode aberrant transcription factors. Several lines of evidence suggest similar pathogenetic mechanisms for these fusion proteins. We used high-density oligonucleotide arrays to identify shared target genes in inducibly transfected U937 cells expressing AML1-ETO, PML-RARalpha, or PLZF-RARalpha. All three fusion proteins significantly repressed the expression of 38 genes and induced the expression of 14 genes. Several of the regulated genes were associated with Wnt signaling. One of these, plakoglobin (gamma-catenin), was induced on the mRNA and protein level by all three fusion proteins. In addition, primary AML blasts carrying one of the fusion proteins significantly overexpressed plakoglobin. The plakoglobin promoter was cloned and shown to be induced by AML1-ETO, with promoter activation depending on the corepressor and histone deacetylase binding domains. The induction of plakoglobin by AML fusion proteins led to downstream signaling and transactivation of TCF- and LEF-dependent promoters, including the c-myc promoter, which was found to be bound by plakoglobin in vivo after AML1-ETO expression. beta-Catenin protein levels and TCF and LEF target genes such as c-myc and cyclin D1 were found to be induced by the fusion proteins. On the functional level, a dominant negative TCF inhibited colony growth of AML1-ETO-positive Kasumi cells, whereas plakoglobin transfection into myeloid 32D cells enhanced proliferation and clonal growth. Injection of plakoglobin-expressing 32D cells into syngeneic mice accelerated the development of leukemia. Transduction of plakoglobin into primitive murine hematopoietic progenitor cells preserved the immature phenotype during colony growth, suggesting enhanced self-renewal. These data provide evidence that activation of Wnt signaling is a common feature of several balanced translocations in AML.

Project description:Notwithstanding the introduction of Tyrosine Kinase Inhibitors (TKIs) revolutionized the outcome of Chronic Myeloid Leukemia (CML), one third of patients still suspends treatment for failure response. Recent research demonstrated that several BCR/ABL1-independent mechanisms can sustain resistance, but the relationship between these mechanisms and the outcome has not yet been fully understood. This study was designed to evaluate in a "real-life" setting if a change of expression of several genes involved in the WNT/BETA-CATENIN, JAK-STAT, and POLYCOMB pathways might condition the outcome of CML patients receiving TKIs. Thus, the expression of 255 genes, related to the aforementioned pathways, was measured by quantitative PCR after 6 months of therapy and compared with levels observed at diagnosis in 11 CML patients, in order to find possible correlations with quality of response to treatment and event-free-survival (EFS). These results were then re-analyzed by the principal component method (PCA) for tempting to better cluster resistant cases. After 12 months of therapy, 6 patients achieved an optimal response and 5 were "resistant;" after application of both statistical methods, it was evident that in all pathways a significant overall up-regulation occurred, and that WNT was the pathway mostly responsible for the TKIs resistance. Indeed, 100% of patients with a "low" up-regulation of this pathway achieved an optimal response vs. 33% of those who showed a "high" gene over-expression (p = 0.016). Analogously, the 24-months EFS resulted significantly influenced by the degree of up-regulation of the WNT signaling: all patients with a "low" up-regulation were event-free vs. 33% of those who presented a "high" gene expression (p = 0.05). In particular, the PCA analysis confirmed the role of WNT pathway and showed that the most significantly up-regulated genes with negative prognostic value were DKK, WNT6, WISP1, and FZD8. In conclusion, our results sustain the need of a wide and multitasking approach in order to understand the resistance mechanisms in CML.

Dataset Information

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

Publications

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

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