Abstract
BackgroundElevated protein expressions of CD markers such as IL2RA/CD25, CXCR4/CD184, CD34 and CD56 are associated with adverse prognosis in acute myeloid leukemia (AML). However, the prognostic value of mRNA expressions of these CD markers in AML remains unclear. Through our pilot evaluation, IL2RA mRNA expression appeared to be the best candidate as a prognostic biomarker. Therefore, the aim of this study is to characterize the prognostic value of IL2RA mRNA expression and evaluate its potential to refine prognostification in AML.MethodsIn a cohort of 239 newly diagnosed AML patients, IL2RA mRNA expression were measured by TaqMan realtime quantitative PCR. Morphological, cytogenetics and mutational analyses were also performed. In an intermediate-risk AML cohort with 66 patients, the mRNA expression of prognostic biomarkers (BAALC, CDKN1B, ERG, MECOM/EVI1, FLT3, ID1, IL2RA, MN1 and WT1) were quantified by NanoString technology. A TCGA cohort was analyzed to validate the prognostic value of IL2RA. For statistical analysis, Mann–Whitney U test, Fisher exact test, logistic regression, Kaplan–Meier and Cox regression analyses were used.ResultsIn AML cohort of 239 patients, high IL2RA mRNA expression independently predicted shorter relapse free survival (RFS, p < 0.001) and overall survival (OS, p < 0.001) irrespective of age, cytogenetics, FLT3-ITD or c-KIT D816V mutational status. In core binding factor (CBF) AML, high IL2RA mRNA expression correlated with FLT3-ITD status (p = 0.023). Multivariable analyses revealed that high IL2RA expression (p = 0.002), along with c-KIT D816V status (p = 0.013) significantly predicted shorter RFS, whereas only high IL2RA mRNA expression (p = 0.014) significantly predicted shorter OS in CBF AML. In intermediate-risk AML in which multiple gene expression markers were tested by NanoString, IL2RA significantly correlated with ID1 (p = 0.006), FLT3 (p = 0.007), CDKN1B (p = 0.033) and ERG (p = 0.030) expressions. IL2RA (p < 0.001) and FLT3 (p = 0.008) expressions remained significant in predicting shorter RFS, whereas ERG (p = 0.008) and IL2RA (p = 0.044) remained significant in predicting shorter OS. Similar analyses in TCGA intermediate-risk AML showed the independent prognostic role of IL2RA in predicting event free survival (p < 0.001) and OS (p < 0.001).ConclusionsHigh IL2RA mRNA expression is an independent and adverse prognostic factor in AML and specifically stratifies patients to worse prognosis in both CBF and intermediate-risk AML.
Highlights
Elevated protein expressions of cluster of differentiation (CD) markers such as interleukin 2 receptor subunit alpha (IL2RA)/CD25, C-X-C chemokine receptor type 4 (CXCR4)/CD184, CD34 and CD56 are associated with adverse prognosis in acute myeloid leukemia (AML)
The pilot study revealed the mRNA expressions of IL2RA is the most suitable prognostic CD marker gene In order to determine the suitable prognostic biomarker candidate genes, we performed initial evaluation of both mRNA as well as protein levels on four CD marker genes (IL2RA, CXCR4, CD56 and CD34)
The IL2RA mRNA and its protein CD25 levels were assayed in 54 primary AML bone marrow (BM) samples by TaqMan realtime quantitative-polymerase chain reaction (RQ-PCR) and flow cytometry (FCM) respectively, in which the mRNA level was shown as 2 −∆cycle threshold (Ct) of IL2RA gene relative to ABL1 gene and the expression level of CD25 protein was illustrated as percentage in leukemia blast cells
Summary
Elevated protein expressions of CD markers such as IL2RA/CD25, CXCR4/CD184, CD34 and CD56 are associated with adverse prognosis in acute myeloid leukemia (AML). In the current risk stratification system, recurrent genetic abnormalities stratify AML into three risk status categories including favourable-risk, intermediate-risk and poor-risk [1] This risk stratification system, together with clinical characteristics of AML patients such as age and medical comorbid, dictates the prognosis of each individual patient, as well as guide physicians to decide appropriate treatment regimens [1]. In addition to the well-established recurrent cytogenetic aberrations and molecular mutations, genes with aberrant expression at protein or mRNA level have been shown to have significant prognostic values in AML over the last decade [2] These gene expression biomarkers help shed light on mechanisms of development and progression of this largely heterogeneous malignancy, but more importantly help clinicians to refine prognostic tools to improve patient care in clinical practice
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