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High expression of c-kit mRNA predicts unfavorable outcome in adult patients with t(8;21) acute myeloid leukemia.

ABSTRACT: The reason that a certain subgroup of acute myeloid leukemia (AML) patients with t(8;21) translocation (generating the AML1/ETO fusion gene) displays a poor survival remains elusive. The proto-oncogene c-kit is expressed in approximately 80% of AML cases. The kinase domain mutation of the c-kit gene, one of the most common gain-of-function mutations associated with t(8;21) AML, predicts higher relapse risk and poor prognosis. However, the role of c-kit high expression in t(8;21) AML remains poorly understood. Here we evaluated the prognostic significance of c-kit expression levels in AML patients. The mRNA expression of c-kit was determined by real-time quantitative reverse transcription PCR in 132 adult AML patients. Patients were grouped into quartiles according to c-kit expression levels (Q1-Q4, each quartile containing 25% of patients) and divided into c-kit high (Q4; n = 33) and c-kit low (Q1-Q3; n = 99). High c-kit expression was associated with AML1/ETO-positive and with c-kit mutation. Of note, 35.8% of the AML1/ETO-positive AML patients carrying wild-type c-kit expressed high levels of c-kit, suggesting that other factors are involved in c-kit overexpression. High c-kit expression was associated with inferior overall and event-free survival in AML1/ETO-positive patients and was independently predictive for overall and event-free survival in multivariate analyses in a c-kit mutation-independent manner. Thus, high c-kit expression serves as a reliable molecular marker for poor prognosis, supporting a pathogenetic role of c-kit signaling in AML1/ETO-positive AML. AML1/ETO-positive patients with high c-kit expression might benefit from early treatment modifications and molecular target therapies.

SUBMITTER: Gao X

PROVIDER: S-EPMC4393018 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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High expression of c-kit mRNA predicts unfavorable outcome in adult patients with t(8;21) acute myeloid leukemia.

Gao Xiaoning X Lin Ji J Gao Li L Deng Ailing A Lu Xiaolin X Li Yonghui Y Wang Lili L Yu Li L

PloS one 20150410 4

The reason that a certain subgroup of acute myeloid leukemia (AML) patients with t(8;21) translocation (generating the AML1/ETO fusion gene) displays a poor survival remains elusive. The proto-oncogene c-kit is expressed in approximately 80% of AML cases. The kinase domain mutation of the c-kit gene, one of the most common gain-of-function mutations associated with t(8;21) AML, predicts higher relapse risk and poor prognosis. However, the role of c-kit high expression in t(8;21) AML remains poor ...[more]

PMID: 25860287

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Project description:AimAcute myeloid leukemia (AML) is a heterogeneous disorder with complex genetic basis and adverse prognosis. Cytogenetics risk, somatic mutations and gene expression profiles are important prognostic factors for AML patients. However, accurate stratification of patient prognosis remains an unsolved problem in AML. This study was to to develop a novel gene profile to accurately classify AML patients into subgroups with different survival probabilities.MethodsSurvival-related genes were determined by Kaplan-Meier survival analysis and multivariate analysis using the expression and clinical data of 405 AML patients from Oregon Health & Science University (OHSU) dataset and validated in The Cancer Genome Atlas (TCGA) database. Feature selection was performed by using the Least Absolute Shrinkage and Selection Operator (LASSO) method. With the LASSO model, a prognostic 85-gene score was established and compared with 2 known gene-expression risk scores. The stratification of AML patients was performed by unsupervised hierarchical clustering of 85 gene expression levels to identify clusters of AML patients with different survival probabilities.ResultsThe LASSO model comprising 85 genes was considered as the optimal model based on relatively high area under curve value (0.83) and the minimum mean squared error. The 85-gene score was associated with increased mortality in AML patients. Hierarchical clustering analysis of the 85 genes revealed 3 subgroups of AML patients in the OHSU dataset. The cluster1 AML patients were associated with more female cases, higher percent of bone marrow blast cells, 85-gene score, cytogenetics risk, more frequent FLT3-ITD, DNMT3A, NP1 mutations, less frequent TP53, RUNX1 mutations, poorer overall survival than cluster2 tumors. The 85-gene score had higher AUC (0.75) than the 5-gene risk score and LSC17 score (0.74 and 0.65).ConclusionsThe 85-gene score is superior to the 2 established prognostic gene signatures in the prediction of prognosis of AML patients.

Project description:BackgroundAcute myeloid leukemia (AML) with t(8;21) needs to be further stratified. In addition to leukemia cells, immune cells in tumor microenvironment participate in tumor initiation, growth and progression. Interleukins (ILs)/interleukin receptors (ILRs) interaction plays important roles in the antitumor immune response. IL7R is reported to be relevant to prognosis in solid tumor and acute lymphoblastic leukemia. However, the prognostic significance of IL7R in t(8;21) AML remains to be clarified.MethodsBone marrows collected from 156 newly diagnosed t(8;21) AML patients were used for testing IL7R transcript level by TaqMan-based real-time quantitative PCR (RQ-PCR), and RNAseq were performed in 15 of them. Moreover, IL7R expression at diagnosis were measured by RQ-PCR and flow cytometry (FCM) simultaneously in other 13 t(8;21) AML patients.Resultst(8;21) AML patients had varied IL7R transcript levels and were categorized into low-expression (IL7R-L) and high-expression (IL7R-H) groups; IL7R-L was significantly associated with a lower relapse-free survival (RFS) rate (P=0.0027) and KITD816/D820 mutation (P=0.0010). Furthermore, IL7R-L was associated with a lower RFS rate in KITD816/D820 group (P=0.013) and IL7R-H/KITD816/D820 patients had similar RFS to KITN822/e8/WT patients (P=0.35). GO analysis enrichment showed that down-regulated genes were predominantly involved in the regulation of T cell and leukocyte activation, proliferation and differentiation in IL7R-L group. IL7R-L had significantly lower levels of Granzymes A/B, CCR7, CD28 and CD27 than IL7R-H group (all P<0.05). FCM analysis showed IL7R protein was primarily expressed in CD4+ T and CD8+ T cell subset. A significant association was found between the transcript level of IL7R and the percentage of CD8+ T cells in nucleated cells (P=0.015) but not CD4+ T cells (P=0.47).ConclusionLow IL7R transcript level of bone marrow at diagnosis predicted relapse in t(8;21) AML, which might be caused by the difference in the amount, status and function of T cells.

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High expression of c-kit mRNA predicts unfavorable outcome in adult patients with t(8;21) acute myeloid leukemia.

Publications

High expression of c-kit mRNA predicts unfavorable outcome in adult patients with t(8;21) acute myeloid leukemia.

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