Abstract
BackgroundLeukemia stem cell (LSC)-enriched genes have been shown to be highly prognostic in acute myeloid leukemia (AML). However, the prognostic value of tumor suppressor genes (TSGs) that are repressed early in LSC remains largely unknown.MethodsWe compared the public available expression/methylation profiling data of LSCs with that of hematopoietic stem cells (HSCs), in order to identify potential tumor suppressor genes in LSC. The prognostic relevance of PCDH17 was analyzed on a cohort of 173 AML patients from The Cancer Genome Atlas (TCGA), and further validated in three independent cohorts (n = 339).ResultsWe identified protocadherin17 (PCDH17) and demonstrated that it was significantly down-regulated and hypermethylated in LSCs compared with HSCs. Our analyses of primary AML patient samples also confirmed these deregulations. Clinically, low PCDH17 expression was associated with female sex (P = 0.01), higher WBC (P < 0.0001), higher percentages of blasts in bone marrow (BM) and peripheral blood (PB) (P = 0.04 and < 0.001, respectively), presence of FLT3-internal tandem duplications (P = 0.002), mutated NPM1 (P = 0.02), and wild-type TP53 (P = 0.005). Moreover, low PCDH17 expression predicted worse overall survival (OS) in four independent cohorts as well as in the molecularly defined subgroups of AML patients. In multivariable analyses, low PCDH17 expression retained independent prognostic value for OS. Biologically, PCDH17 expression-associated gene signatures were characterized by deregulations of EMT- and Wnt pathway-related genes.ConclusionsPCDH17 gene was silenced by DNA methylation in AML. Low PCDH17 expression is associated with distinct clinical and biological features and improves risk stratification in patients with AML.
Highlights
Leukemia stem cell (LSC)-enriched genes have been shown to be highly prognostic in acute myeloid leukemia (AML)
As described by the latest WHO classification of AML [8], mutations in NPM1 and biallelic mutations of CEBPA in cytogenetically normal patients are associated with a favorable prognosis, whereas RUNX1 mutations have been implicated in worse overall survival in AML patients
Patients and samples To analyze the prognostic impact of PCDH17 in AML patients, four independent cohorts with survival information were included in this study: (1) a discovery cohort including 200 de novo AML patients derived from the The Cancer Genome Atlas (TCGA) AML study [3]; (2) two validation cohorts of 242 cytogenetically normal AML patients described by Metzeler et al [24]; (3) an independent (Chinese) cohort consisted of 184 AML patients enrolled from 2005 to 2016 and treated in the Affiliated People’s Hospital of Jiangsu University
Summary
Leukemia stem cell (LSC)-enriched genes have been shown to be highly prognostic in acute myeloid leukemia (AML). The biological heterogeneity mainly consists of cytogenetic [1], genetic [2, 3], epigenetic [4], and transcriptional diversities [5, 6]. These aberrations together contribute to the clinical heterogeneity of AML, which makes it difficult for risk stratification and targeted therapy of the disease. Karyotypic analysis remains as the mainstay of risk classification in AML, yet 40 to 50% of patients lack clonal chromosome aberrations [1]; molecular markers, Xu et al J Transl Med (2019) 17:102 especially recurrent somatic mutations, have shown their ability to subdivide this large group of patients [7]. Novel biomarkers, like gene expression alterations, are needed to improve outcome prediction in the context of established prognostic markers in AML
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