Background: CXCR4 chemokine receptors play an important role in leukemia proliferation, extramedullary migration, infiltration, adhesion, and resistance to chemotherapy drugs.Methods: The CXCR4 expression by flow cytometry in 122 acute myeloid leukemia (AML) patients between 2010 and 2014 was analyzed.Results: The expression of CXCR4 in AML‐M4/M5 was found to be significantly higher than that of other subtypes according to both FAB subtype and WHO classification. The FLT3‐ITD mutant was significantly higher in high CXCR4 expression group (P = .0086). Our data also showed that CXCR4 expression was correlated with CD64 expression. Low CXCR4 expression on AML cells was associated with better prognosis, and the median overall survival (OS) for low CXCR4 expression patients was 318 days, compared with 206 days for patients with high CXCR4 expression (P = .045). Multivariate analysis revealed that CXCR4 expression, age, and extramedullary infiltration were independent prognostic factors.Conclusions: Our study demonstrated that CXCR4 expression in AML was an independent prognostic predictor for disease survival that could be rapidly and easily determined by flow cytometry at disease presentation.

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). 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. In 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. In 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). High 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.

Resistance to chemotherapy is a major challenge for leukemia treatment. It has been suggested that leukemia stem cells (LSCs), a small pool of self‑renewing leukemic cells, play important roles in development of chemotherapy resistance. The expression of cluster of differentiation 96 (CD96), a potential marker for LSCs, was investigated in CD34+CD38‑ cells of 105 acute leukemia (AL) patients by flow cytometry. The data showed that all the CD34+, CD34+CD38‑ and CD34+CD38‑CD96+ proportions were much higher in AL compared to the normal control (P15% CD34+CD38‑ cells achieved complete remission (CR), suggesting that as an LSC‑rich population, the amount of CD34+CD38‑ cells may not be positively associated with the proportion of refractory LSCs. The mean percentage of the co‑presence of CD96 expression itself was similar in AML patients with CR and non‑CR (P>0.05). However, the CR rate was significantly higher in the AML population with <10% CD96 expressed, which indicated that a distinct sub‑group of CD34+CD38‑CD96+ cells may still contribute to the drug resistance or poor prognosis.

The role of CXC chemokine receptors in tumors has been an increasingly researched focus in recent years. However, significant prognostic values of CXCR members in acute myeloid leukemia are yet to be explored profoundly. In this study, we firstly made an analysis of the relationship of CXCR family members and AML using samples from TCGA. Our results suggested that transcriptional expressions of CXCRs serve an important role in AML. CXCR transcript expressions, except CXCR1 expression, were significantly increased in AML. It displayed the expression pattern of CXCR members in different AML subtypes according to FAB classification. The correlations of CXCR transcript expression with different genotypes and karyotypes were also present. High CXCR2 expression was found to have a significantly worse prognosis compared with that of low CXCR2 expression, and CXCR2 was also found to be an independent prognostic factor. We also established a CXCR signature to identify high-risk subgroups of patients with AML. It was an independent prognostic factor and could become a powerful method to predict the survival rate of patients.