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Genetic mutational profiling analysis of T cell acute lymphoblastic leukemia reveal mutant FBXW7 as a prognostic indicator for inferior survival

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Abstract

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive neoplasm for which there are currently no adequate biomarkers for developing risk-adapted therapeutic regimens to improve the treatment outcome. In this prospective study of 83 Chinese patients (54 children and 29 adults) with de novo T-ALL, we analyzed mutations in 11 T-ALL genes: NOTCH1, FBXW7, PHF6, PTEN, N-RAS, K-RAS, WT1, IL7R, PIK3CA, PIK3RA, and AKT1. NOTCH1 mutations were identified in 51.9 and 37.9 % of pediatric and adult patients, respectively, and these patients showed improved overall survival (OS) and event-free survival (EFS). The FBXW7 mutant was present in 25.9 and 6.9 % of pediatric and adult patients, respectively, and was associated with inferior OS and EFS in pediatric T-ALL. Multivariate analysis revealed that mutant FBXW7 was an independent prognostic indicator for inferior EFS (hazard ratio [HR] 4.38; 95 % confidence interval [CI] 1.15–16.71; p = 0.03) and tended to be associated with reduced OS (HR 2.81; 95 % CI 0.91–8.69; p = 0.074) in pediatric T-ALL. Mutant PHF6 was present in 13 and 20.7 % of our childhood and adult cohorts, respectively, while PTEN mutations were noted in 11.1 % of the pediatric patients. PTEN and NOTCH1 mutations were almost mutually exclusive, while IL7R and WT1 mutations were rare in pediatric T-ALL and PTPN11 and AKT1 mutations were infrequent in adult T-ALL. This study revealed differences in the mutational profiles of pediatric and adult T-ALL and suggests mutant FBXW7 as an independent prognostic indicator for inferior survival in pediatric T-ALL.

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Acknowledgments

We are grateful to the patients, families, and physicians for their participation in the study. The study was supported in part by the Children’s Hospital of Chongqing Medical University (Grant No. ZHYX2013-7).

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The authors declare that they have no conflict of interest.

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    Authors and Affiliations

    1. Center for Clinical Molecular Medicine, Children’s Hospital of Chongqing Medical University, Chongqing, China

      Lan Yuan, Xi Chen, Yi Huang, Xingjuan Wang, Lin Zou & Liming Bao

    2. Ministry of Education Key Laboratory of Child Development and Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China

      Lan Yuan, Xi Chen, Yi Huang, Xingjuan Wang, Lin Zou & Liming Bao

    3. Chongqing Key Laboratory of Pediatrics, Children’s Hospital of Chongqing Medical University, Chongqing, China

      Lan Yuan, Xi Chen, Yi Huang, Xingjuan Wang, Lin Zou & Liming Bao

    4. Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China

      Lan Yuan, Xi Chen, Yi Huang, Xingjuan Wang, Lin Zou & Liming Bao

    5. Departments of Rheumatology and Occupational Medicine and Hematology, Huashan Hospital of Fudan University, Shanghai, China

      Ling Lu

    6. Children’s Hospital of Shanghai Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

      Yongchen Yang & Hengjuan Sun

    7. Department of Pathology and Laboratory Medicine, Geisel School of Medicine Dartmouth College, One Medical Center Drive, Lebanon, NH, 03756, USA

      Liming Bao

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    Lan Yuan and Ling Lu contributed equally to this work.

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    Table S1

    PCR primers and annealing temperatures (PDF 180 kb)

    Table S2

    Genetic aberrations identified in the pediatric T-ALL cohort (PDF 55 kb)

    Table S3

    Genetic aberrations identified in the adult T-ALL cohort (PDF 22 kb)

    Fig. S1

    Survival analyses according to the presence of NOTCH1 mutations in adult T-ALL and the NOTCH1 and FBXW7 mutants in pediatric T-ALL. (a and b) Kaplan-Meier plots of OS and EFS for pediatric T-ALL patients with mutated NOTCH1 and/or mutated FBXW7 and wild-type NOTCH1 and FBXW7. (c) Kaplan-Meier plots of OS for adult T-ALL patients with mutated and wild-type NOTCH1. (JPEG 46 kb)

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    Yuan, L., Lu, L., Yang, Y. et al. Genetic mutational profiling analysis of T cell acute lymphoblastic leukemia reveal mutant FBXW7 as a prognostic indicator for inferior survival. Ann Hematol 94, 1817–1828 (2015). https://doi.org/10.1007/s00277-015-2474-0

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