Secreted-frizzled related protein 1 is a transcriptional repression target of the t(8;21) fusion protein in acute myeloid leukemia

Abstract

Secreted-frizzled related proteins (SFRPs) are modulators of the Wnt signaling pathway that is closely involved in normal and malignant hematopoiesis. Epigenetic deregulation of Wnt modulators leading to aberrant signaling has been reported in adult patients with acute myeloid leukemia (AML), but its occurrence in childhood patients with AML and the role of individual modulators are unclear. In this study, we examined SFRP1, SFRP2, SFRP4, and SFRP5 promoter methylation in 83 patients with AML (59 children and 24 adults) and found preferential SFRP1 methylation and mRNA down-regulation in the prognostically favorable subgroup of AML with t(8;21) translocation. Among the 4 genes, SFRP1 methylation independently predicted prolonged event-free and relapse-free survivals in childhood patients with nonacute promyelocytic leukemia with nonadverse cytogenetics. Mechanistically, we further demonstrated that RUNX1-ETO, the t(8;21) fusion product, specifically bound the SFRP1 promoter and repressed its transcription via a consensus RUNX binding site. In t(8;21)-leukemia cells, SFRP1 selectively inhibited canonical Wnt signaling and cellular proliferation that were associated with concomitant down-regulation of Wnt/␤-catenin target genes, including CCND1 and MYC. Taken IntroductionThe Wnt signaling pathway is an important regulator of hematopoietic cell fate and growth. 1,2 Deregulation of this pathway has been implicated in human leukemogenesis. 3 Wnt signaling comprises the canonical pathway with ␤-catenin as a central mediator and noncanonical pathways primarily involving Ca 2ϩ ions and planar cell polarity. 4 Signal transduction by Wnts is tightly regulated by several families of extracellular modulators, among which secreted frizzled-related proteins (SFRPs) are the largest family. 4 SFRPs are generally regarded as Wnt antagonists. However, they can also activate Wnt signaling and interfere with other signaling pathways through Wnt-independent mechanisms. 4 In humans, 5 SFRP genes (SFRP1, SFRP2, SFRP3, SFRP4, and SFRP5) have been identified, and 4 of these genes except SFRP3 contain dense CpG islands around their promoter regions. Interestingly, previous studies reported that SFRP1, SFRP2, SFRP4, SFRP5, and other Wnt modulators were silenced by promoter hypermethylation in different cancers, including acute myeloid leukemia (AML), and this epigenetic silencing was associated with aberrant Wnt activation. [5][6][7][8] Moreover, in AML, the Wnt signaling can also be activated by mutant fms-like tyrosine kinase 3 (FLT3) and common translocationassociated fusion proteins. 9,10 Collectively, these findings indicate that Wnt signaling aberration involves multiple mechanisms and is a common molecular feature in different biologic subtypes of AML.t(8;21)(q22;q22) is the most frequent karyotypic abnormality in AML, representing ϳ 15% of total cases, and is associated with the French-American-British (FAB) M2 subtype. 11 t(8;21) fuses the N-terminal portion of RUNX1, including its Runt domain, to most of the eight-twenty-one (E...

Low SFRP1 Expression Correlates with Poor Prognosis and Promotes Cell Invasion by Activating the Wnt/β-Catenin Signaling Pathway in NPC

“…SFRP1 is hypermethylated and downregulated in various cancers, including breast (34), colorectal (35), and ovarian cancer (36). SFRP1 hypermethylation and downregulation are also associated with poor prognosis in several tumors (34,37,38). Moreover, SFRP1 is associated with tumor chemotherapy, and some antitumor drugs inhibit cell growth through the re-expression of SFRP1 (39)(40)(41).…”

Wnt Signaling in Cancer

“…Considering that DNA hypermethylation of promotor regions is frequently accompanied by chromatin modifications, it is not surprising that the sSFRP1 gene is also a target of chromatin modifying factors (McGarvey et al 2006). In the case of AML, it was proposed that chromatin modification resulted from the targeting of the sFRP1 gene by the RUNX-ETO fusion protein (Cheng et al 2011b). A RUNX binding site was identified in the 5 0 regulatory region of the sFRP1 gene and this region was also detected in chromatin immunoprecipitated with antibodies specific to ETO.…”

Chemotherapy-induced hypomethylation of N-myc downstream-regulated gene 4 in the bone marrow of patients with acute myeloid leukemia

“…AML with t(8;21)(q22;q22) is the most common karyotypic abnormality observed in AML, comprising ~15% of total cases (20). The incidence of t(8;21) in M2 was 24.1% (21), and it was typically considered to be among the most favorable subtypes for predicting a high response to treatment (~60%) (22).…”