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Gene mutation profile and risk stratification in AML1?ETO?positive acute myeloid leukemia based on next?generation sequencing.

ABSTRACT: Gene mutations play an important role in the development and progression of AML1?ETO?positive acute myeloid leukemia (AE?AML). Nevertheless, the gene mutation profile in this subtype of leukemia remains unclear. In addition, the clinical and prognostic effects of different mutant genes may be underestimated. In the present study, gene sequencing was conducted at diagnosis and relapse with next?generation sequencing (NGS) in 64 patients with newly diagnosed AE?AML, and 44/64 (68.8%) patients were found to present with a median of 2 (1?10) recurrent mutations at diagnosis and 6/11 (54.5%) cases were found to present with genetic alterations at relapse. c?KIT mutation was the most common in this cohort, with an incidence of 27/64 (42.2%) at diagnosis, followed by ASXL1 (n=10, 15.6%), MET (n=8, 12.5%), MLH1 (n=6, 9.4%), TET2 (n=5, 7.8%), and FBXW7, TP53 and DNMT3A (n=5, 7.8%). Survival analysis showed that c?KIT (exon 8, 17) but not exon 10 adversely affected survival. In addition, ASXL1 and TP53 were poor impact factors for recurrence?free survival (RFS) (P<0.05), and ASXL1, MET, FBXW7 and TP53 had a negative impact on overall survival (OS) (P<0.05). Multivariate analysis showed that c?KIT (exon 8, 17) [RFS: hazard ratio (HR) 3.36, 95% confidence interval (CI) 1.54?7.34, P=0.002; OS: HR 2.84, 95% CI 1.20?6.71, P=0.018] and ASXL1 mutations (RFS: HR 3.13, 95% CI 1.34?7.32, P=0.009; OS: HR 3.94, 95% CI 1.62?9.61, P=0.003) were independent adverse factors for survival. Further, co?mutation of these two genes showed even worse effect on disease outcome. Collectively, additional gene mutations play critical role in AE?AML. C?KIT and ASXL1 mutations are the two most common mutations in this subtype of leukemia. C?KIT (exon 8, 17) but not exon 10, and also the ASXL1 mutation poorly affect the disease outcome of this disease.

SUBMITTER: Yu G

PROVIDER: S-EPMC6826310 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Gene mutation profile and risk stratification in AML1‑ETO‑positive acute myeloid leukemia based on next‑generation sequencing.

Yu Guopan G Yin Changxin C Wu Fuqun F Jiang Ling L Zheng Zhongxin Z Xu Dan D Zhou Jiaheng J Jiang Xuejie X Liu Qifa Q Meng Fanyi F

Oncology reports 20191015 6

Gene mutations play an important role in the development and progression of AML1‑ETO‑positive acute myeloid leukemia (AE‑AML). Nevertheless, the gene mutation profile in this subtype of leukemia remains unclear. In addition, the clinical and prognostic effects of different mutant genes may be underestimated. In the present study, gene sequencing was conducted at diagnosis and relapse with next‑generation sequencing (NGS) in 64 patients with newly diagnosed AE‑AML, and 44/64 (68.8%) patients were ...[more]

PMID: 31638252

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Project description:Backgroundt(8;21)(q22;q22) is one of the most frequent chromosomal abnormalities in acute myeloid leukemia (AML), leading to the generation of the fusion protein AML1-ETO. Despite t(8;21) AML being considered as a subtype with a favorable prognosis, approximately 30-50% of patients experience drug resistance and subsequent relapse. N6-methyladenosine (m6A) is demonstrated to be involved in the development of AML. However, the regulatory mechanisms between AML1-ETO and m6A-related enzymes and the roles of dysregulated m6A modifications in the t(8;21)-leukemogenesis and chemoresistance remain elusive.MethodsChromatin immunoprecipitation, dual-luciferase reporter assay, m6A-qPCR, RNA immunoprecipitation, and RNA stability assay were used to investigate a regulatory loop between AML1-ETO and FTO, an m6A demethylase. Gain- and loss-of-function experiments both in vitro and in vivo were further performed. Transcriptome-wide RNA sequencing and m6A sequencing were conducted to identify the potential targets of FTO.ResultsHere we show that FTO is highly expressed in t(8;21) AML, especially in patients with primary refractory disease. The expression of FTO is positively correlated with AML1-ETO, which is attributed to a positive regulatory loop between the AML1-ETO and FTO. Mechanistically, AML1-ETO upregulates FTO expression through inhibiting the transcriptional repression of FTO mediated by PU.1. Meanwhile, FTO promotes the expression of AML1-ETO by inhibiting YTHDF2-mediated AML1-ETO mRNA decay. Inactivation of FTO significantly suppresses cell proliferation, promotes cell differentiation and renders resistant t(8;21) AML cells sensitive to Ara-C. FTO exerts functions by regulating its mRNA targets, especially IGFBP2, in an m6A-dependent manner. Regain of Ara-C tolerance is observed when IGFBP2 is overexpressed in FTO-knockdown t(8;21) AML cells.ConclusionOur work reveals a therapeutic potential of targeting AML1-ETO/FTO/IGFBP2 minicircuitry in the treatment for t(8;21) patients with resistance to Ara-C.

Dataset Information

Gene mutation profile and risk stratification in AML1?ETO?positive acute myeloid leukemia based on next?generation sequencing.

Publications

Gene mutation profile and risk stratification in AML1‑ETO‑positive acute myeloid leukemia based on next‑generation sequencing.

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