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Companion gene mutations and their clinical significance in AML with double mutant CEBPA

Cancer Gene Therapy volume 27, pages 599–606 (2020)Cite this article

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Abstract

Acute myeloid leukemia (AML) with double mutant CEBPA (CEBPAdm) is generally associated with favorable prognosis, but the heterogeneity still blatant and needs further exploration. We aimed to comprehensively analyze the companion genetic abnormalities and their clinical significance in AML patients with CEBPAdm. By performed targeted amplicon sequencing of 58 genes in specimens at the time of initial diagnosis of 609 AML patients, we identified 76 cases (12.5%) were CEBPAdm, and 88.2% of them also carry other gene mutations. There were more additional gene mutations, especially more epigenetic modifiers gene mutations in CEBPAsm than CEBPAdm cases, while GATA2, CSF3R, JAK3, and KIT mutations were exclusively betide in CEBPAdm but not CEBPAsm. Mutations of tyrosine kinase genes confer to adverse prognostic in karyotype normal CEBPAdm AML and provide potential therapeutic targets. The incidence of germline CEBPA mutation in CEBPAdm cases was 5.3% (4/76), including one C-terminal mutation. Deciphering the mutation spectrum of CEBPAdm AML could facilitate an in-depth understanding of the pathogenesis and refine the prognostic classification of this disease entity.

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References

  1. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405.

    Article  CAS  Google Scholar 

  2. Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–47.

    Article  Google Scholar 

  3. Tallman MS, Wang ES, Altman JK, Appelbaum FR, Bhatt VR, Bixby D, et al. Acute Myeloid Leukemia, Version 3.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2019;17:721–49.

  4. Dufour A, Schneider F, Metzeler KH, Hoster E, Schneider S, Zellmeier E, et al. Acute myeloid leukemia with biallelic CEBPA gene mutations and normal karyotype represents a distinct genetic entity associated with a favorable clinical outcome. J Clin Oncol. 2010;28:570–7.

    Article  CAS  Google Scholar 

  5. Grossmann V, Haferlach C, Nadarajah N, Fasan A, Weissmann S, Roller A, et al. CEBPA double-mutated acute myeloid leukaemia harbours concomitant molecular mutations in 76.8% of cases with TET2 and GATA2 alterations impacting prognosis. Br J Haematol. 2013;161:649–58.

    Article  CAS  Google Scholar 

  6. Taskesen E, Bullinger L, Corbacioglu A, Sanders MA, Erpelinck CA, Wouters BJ, et al. Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity. Blood. 2011;117:2469–75.

    Article  CAS  Google Scholar 

  7. Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114:937–51.

    Article  CAS  Google Scholar 

  8. Zhang Y, Wang F, Chen X, Zhang Y, Wang M, Liu H, et al. CSF3R Mutations are frequently associated with abnormalities of RUNX1, CBFB, CEBPA, and NPM1 genes in acute myeloid leukemia. Cancer-Am Cancer Soc. 2018;124:3329–38.

    CAS  Google Scholar 

  9. Wouters BJ, Lowenberg B, Erpelinck-Verschueren CA, van Putten WL, Valk PJ, Delwel R. Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acute myeloid leukemia with a distinctive gene expression profile that is uniquely associated with a favorable outcome. Blood. 2009;113:3088–91.

    Article  CAS  Google Scholar 

  10. Su L, Tan Y, Lin H, Liu X, Yu L, Yang Y, et al. Mutational spectrum of acute myeloid leukemia patients with double CEBPA mutations based on next-generation sequencing and its prognostic significance. Oncotarget. 2018;9:24970–9.

    Article  Google Scholar 

  11. Fasan A, Haferlach C, Alpermann T, Jeromin S, Grossmann V, Eder C, et al. The role of different genetic subtypes of CEBPA mutated AML. Leukemia. 2014;28:794–803.

    Article  CAS  Google Scholar 

  12. Konstandin NP, Pastore F, Herold T, Dufour A, Rothenberg-Thurley M, Hinrichsen T, et al. Genetic heterogeneity of cytogenetically normal AML with mutations of CEBPA. Blood Adv. 2018;2:2724–31.

    Article  CAS  Google Scholar 

  13. Lavallee VP, Krosl J, Lemieux S, Boucher G, Gendron P, Pabst C, et al. Chemo-genomic interrogation of CEBPA mutated AML reveals recurrent CSF3R mutations and subgroup sensitivity to JAK inhibitors. Blood. 2016;127:3054–61.

    Article  CAS  Google Scholar 

  14. Maxson JE, Ries RE, Wang YC, Gerbing RB, Kolb EA, Thompson SL, et al. CSF3R mutations have a high degree of overlap with CEBPA mutations in pediatric AML. Blood. 2016;127:3094–8.

    Article  Google Scholar 

  15. Maxson JE, Gotlib J, Pollyea DA, Fleischman AG, Agarwal A, Eide CA, et al. Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. N Engl J Med. 2013;368:1781–90.

    Article  CAS  Google Scholar 

  16. Jeong EG, Kim MS, Nam HK, Min CK, Lee S, Chung YJ, et al. Somatic mutations of JAK1 and JAK3 in acute leukemias and solid cancers. Clin Cancer Res 2008;14:3716–21.

    Article  CAS  Google Scholar 

  17. Lennartsson J, Ronnstrand L. Stem cell factor receptor/c-Kit: from basic science to clinical implications. Physiol Rev. 2012;92:1619–49.

    Article  CAS  Google Scholar 

  18. Fasan A, Eder C, Haferlach C, Grossmann V, Kohlmann A, Dicker F, et al. GATA2 mutations are frequent in intermediate-risk karyotype AML with biallelic CEBPA mutations and are associated with favorable prognosis. Leukemia. 2013;27:482–5.

    Article  CAS  Google Scholar 

  19. Marceau-Renaut A, Guihard S, Castaigne S, Dombret H, Preudhomme C, Cheok M. Classification of CEBPA mutated acute myeloid leukemia by GATA2 mutations. Am J Hematol. 2015;90:E93–E94.

    Article  CAS  Google Scholar 

  20. Theis F, Corbacioglu A, Gaidzik VI, Paschka P, Weber D, Bullinger L, et al. Clinical impact of GATA2 mutations in acute myeloid leukemia patients harboring CEBPA mutations: a study of the AML study group. Leukemia. 2016;30:2248–50.

    Article  CAS  Google Scholar 

  21. El-Sharkawi D, Sproul D, Allen CG, Feber A, Wright M, Hills RK, et al. Variable outcome and methylation status according to CEBPA mutant type in double-mutated acute myeloid leukemia patients and the possible implications for treatment. Haematologica. 2018;103:91–100.

    Article  CAS  Google Scholar 

  22. Tien FM, Hou HA, Tang JL, Kuo YY, Chen CY, Tsai CH, et al. Concomitant WT1 mutations predict poor prognosis in acute myeloid leukemia patients with double mutant CEBPA. Haematologica. 2018;103:e510–e513.

    Article  CAS  Google Scholar 

  23. Su L, Gao S, Tan Y, Lin H, Liu X, Liu S, et al. CSF3R mutations were associated with an unfavorable prognosis in patients with acute myeloid leukemia with CEBPA double mutations. Ann Hematol. 2019;98:1641–6.

    Article  CAS  Google Scholar 

  24. Green CL, Koo KK, Hills RK, Burnett AK, Linch DC, Gale RE. Prognostic significance of CEBPA mutations in a large cohort of younger adult patients with acute myeloid leukemia: impact of double CEBPA mutations and the interaction with FLT3 and NPM1 mutations. J Clin Oncol. 2010;28:2739–47.

    Article  CAS  Google Scholar 

  25. Pabst T, Eyholzer M, Haefliger S, Schardt J, Mueller BU. Somatic CEBPA mutations are a frequent second event in families with germline CEBPA mutations and familial acute myeloid leukemia. J Clin Oncol. 2008;26:5088–93.

    Article  CAS  Google Scholar 

  26. Tawana K, Wang J, Renneville A, Bodor C, Hills R, Loveday C, et al. Disease evolution and outcomes in familial AML with germline CEBPA mutations. Blood. 2015;126:1214–23.

    Article  CAS  Google Scholar 

  27. Kim HS, Han E, Jang W, Kim M, Kim Y, Han K, et al. Germline CEBPA mutations in Korean patients with acute myeloid leukemia. Leuk Res. 2019;76:84–86.

    Article  CAS  Google Scholar 

  28. Gutman JA, Hoffner B. A novel CCAAT/enhancer binding protein α germline variant in a case of acute myeloid leukemia. Leuk Lymphoma. 2012;53:1006–7.

    Article  CAS  Google Scholar 

  29. Pathak A, Seipel K, Pemov A, Dewan R, Brown C, Ravichandran S, et al. Whole exome sequencing reveals a C-terminal germline variant in CEBPA-associated acute myeloid leukemia: 45-year follow up of a large family. Haematologica. 2016;101:846–52.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Yuanli Xu, Yongxin Guo, Yincheng Tan, Xiaoming Zhang, Xiaoliang Wang, and Jiancheng Fang from Pathology & Laboratory Medicine Division of Hebei Yanda Lu Daopei Hospital for technical support. We thank Yanli Zhao, Yue Lu, Xingyu Cao, Jiarui Zhou, Ruijuan Sun, Jianping Zhang, Zhijie Wei, Min Xiong of Bone Marrow Transplantation Department and Xian Zhang, Junfang Yang, Fanyong Lv of Hematology Department of Hebei Yanda Lu Daopei Hospital for patients and samples supports.

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Authors and Affiliations

  1. Beijing Lu Daopei Institute of Hematology, Beijing, 100076, China

    Yang Zhang, Peihua Lu & Hongxing Liu

  2. Divison of Pathology & Laboratory Medicine, Hebei Yanda Lu Daopei Hospital, Langfang, 065201, China

    Yang Zhang, Fang Wang, Xue Chen, Yu Zhang, Mingyu Wang, Hong Liu, Wen Teng, Panxiang Cao, Daijing Nie, Xiaoli Ma, Tong Wang & Hongxing Liu

  3. Divison of Pathology & Laboratory Medicine, Beijing Lu Daopei Hospital, Beijing, 100076, China

    Tong Wang & Hongxing Liu

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Zhang, Y., Wang, F., Chen, X. et al. Companion gene mutations and their clinical significance in AML with double mutant CEBPA. Cancer Gene Ther 27, 599–606 (2020). https://doi.org/10.1038/s41417-019-0133-7

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