Peipei Lin1,2,3, Yingwan Luo1,2,3, Shuanghong Zhu1,2,3, Dominic Maggio4, Haiyang Yang1,2,3, Chao Hu1,3, Jinghan Wang1,3, Hua Zhang1,2,3, Yanling Ren1,2,3, Xinping Zhou1,2,3, Chen Mei1,2,3, Liya Ma1,2,3, Weilai Xu1,2,3, Li Ye1,2,3, Zhengping Zhuang4, Jie Jin1,3, Hongyan Tong5,6,7. 1. Department of Hematology, The First Affiliated Hospital, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003, People's Republic of China. 2. Myelodysplastic Syndromes Diagnosis and Therapy center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China. 3. Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China. 4. Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. 5. Department of Hematology, The First Affiliated Hospital, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003, People's Republic of China. tonghongyan@zju.edu.cn. 6. Myelodysplastic Syndromes Diagnosis and Therapy center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China. tonghongyan@zju.edu.cn. 7. Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China. tonghongyan@zju.edu.cn.
Abstract
PURPOSE: The myelodysplastic syndromes (MDS) are a group of hematologic disorders characterized by the presence of somatically mutated hematopoietic stem cells (HSCs) that increase the risk of progression to secondary acute myeloid leukemia (sAML). Mutations in isocitrate dehydrogenase (IDHmut) are thought to correlate with the increased production of the oncogenic protein 2-hydroxyglutarate (2-HG) in AML. The aim of this study was to examine whether serum 2-HG has utility as a prognostic biomarker, and whether elevated 2-HG levels are predictive of IDH mutations in patients with MDS. METHODS: Genetic profiling was utilized to determine the genetic composition of a large cohort of MDS patients, including the presence or absence of IDH1 or IDH2 mutations (n = 281). Serum 2-HG levels were detected by liquid chromatography-tandem mass spectrometry. RESULTS: In the current study of MDS patients, elevated serum 2-HG levels were predictive of inferior overall- and leukemia-free survival irrespective of IPSS risk grouping. Higher serum 2-HG levels predicted the presence of IDH mutations. IDH2mut patients had a higher risk of leukemic transformation. The co-occurrence of DNMT3A or SRSF2 mutations was found to be increased in IDH2mut patients. IDH2 mutations were associated with significantly worse OS and LFS amongst patients with low-risk MDS by IPSS grouping. CONCLUSIONS: The noted predictive value of serum 2-HG levels and IDH2 mutations on OS and LFS support the use of biomarkers and/or underlying cytogenetics in novel prognostic scoring systems for MDS.
PURPOSE: The myelodysplastic syndromes (MDS) are a group of hematologic disorders characterized by the presence of somatically mutated hematopoietic stem cells (HSCs) that increase the risk of progression to secondary acute myeloid leukemia (sAML). Mutations in isocitrate dehydrogenase (IDHmut) are thought to correlate with the increased production of the oncogenic protein 2-hydroxyglutarate (2-HG) in AML. The aim of this study was to examine whether serum 2-HG has utility as a prognostic biomarker, and whether elevated 2-HG levels are predictive of IDH mutations in patients with MDS. METHODS: Genetic profiling was utilized to determine the genetic composition of a large cohort of MDS patients, including the presence or absence of IDH1 or IDH2 mutations (n = 281). Serum 2-HG levels were detected by liquid chromatography-tandem mass spectrometry. RESULTS: In the current study of MDS patients, elevated serum 2-HG levels were predictive of inferior overall- and leukemia-free survival irrespective of IPSS risk grouping. Higher serum 2-HG levels predicted the presence of IDH mutations. IDH2mut patients had a higher risk of leukemic transformation. The co-occurrence of DNMT3A or SRSF2 mutations was found to be increased in IDH2mut patients. IDH2 mutations were associated with significantly worse OS and LFS amongst patients with low-risk MDS by IPSS grouping. CONCLUSIONS: The noted predictive value of serum 2-HG levels and IDH2 mutations on OS and LFS support the use of biomarkers and/or underlying cytogenetics in novel prognostic scoring systems for MDS.
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