Deciphering the role of Wnt signaling in acute myeloid leukemia prognosis: how alterations in DNA methylation come into
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REVIEW – CANCER RESEARCH
Deciphering the role of Wnt signaling in acute myeloid leukemia prognosis: how alterations in DNA methylation come into play in patients’ prognosis Andrés Cardona‑Echeverry1 · Jeanette Prada‑Arismendy1 Received: 6 November 2019 / Accepted: 21 September 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Acute myeloid leukemia (AML) is a malignant clonal disorder affecting myeloid differentiation through mechanisms that include epigenetic dysregulation. Abnormal changes in DNA methylation and gene expression profiles of pathways involved in hematopoietic development, such as Wnt/β-catenin, contribute to the transformation, development, and maintenance of leukemic cells. This review summarizes the alterations of Wnt signaling-related genes at the epigenetic and transcriptional level and their implications for AML prognosis. Among the implications of epigenetic alterations in AML, methylation of Wnt antagonists is related to poor prognosis, whereas their upregulation has been associated with a better clinical outcome. Furthermore, Wnt target genes c-Myc and LEF-1 present distinct implications. LEF-1 expression positively influences the patient overall survival. c-Myc upregulation has been associated with treatment resistance in AML, although c-Myc expression is not exclusively dependent of Wnt signaling. Understanding the signaling abnormalities could help us to further understand leukemogenesis, improve the current risk stratification for AML patients, and even serve to propose novel therapeutic targets. Keywords Acute myeloid leukemia · Wnt/β-catenin · Methylation · Gene expression · Prognosis
Introduction Acute myeloid leukemia (AML) is a clonal disorder characterized by an impaired differentiation of myeloid cells. Undifferentiated precursors or blasts gain clonal characteristics replacing healthy hematopoietic components of the bone marrow, peripheral blood, and other tissues (Ferrara and Schiffer 2013; Döhner et al. 2015). The development of AML has various risk factors including chromosomal alterations, Fanconi anemia, physical and chemical exposures; furthermore, AML could be linked to alterations in polymorphic variants in genes related to genomic maintenance, integrity and DNA repair (D’Alò * Jeanette Prada‑Arismendy [email protected] Andrés Cardona‑Echeverry [email protected] 1
Grupo de Investigación e innovación Biomédica‑GI2B, Facultad de Ciencias Exactas y Aplicadas, Instituto Tecnológico Metropolitano-ITM, 050034 Medellín, Colombia
et al. 2004; Schnatter et al. 2005; Bowen 2006; Deschler and Lübbert 2006; Voso et al. 2007, 2008; Hamdy et al. 2011; Xiao et al. 2014; El-Tokhy et al. 2014; Lu et al. 2015; Bănescu et al. 2016; Staal et al. 2016). In addition to genetic and cytogenetic complexity, the patients’ age impacts the outcome (Schoch et al. 2004). Treatment effectiveness reaches 35–40% in patients who are 60 years of age or younger, while this proportion decreases to 5–15% in patients older than 60 years (Döhner et al. 2010, 20
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