Skip to main content
SpringerLink
Log in

GATA2 mutations in patients with acute myeloid leukemia-paired samples analyses show that the mutation is unstable during disease evolution

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

Recently, mutations of the GATA binding protein 2 (GATA2) gene were identified in acute myeloid leukemia (AML) patients with CEBPA double mutations (CEBPA double-mut), but the interaction of this mutation with other genetic alterations and its dynamic changes during disease progression remain to be determined. In this study, 14 different missense GATA2 mutations, which were all clustered in the highly conserved N-terminal zinc finger 1 domain, were identified in 27.4, 6.7, and 1 % of patients with CEBPA double-mut, CEBPA single-mut, and CEBPA wild type, respectively. All but one patient with GATA2 mutation had concurrent CEBPA mutation. GATA2 mutations were closely associated with younger age, FAB M1 subtype, intermediate-risk cytogenetics, expression of HLA-DR, CD7, CD15, or CD34 on leukemic cells, and CEBPA mutation, but negatively associated with FAB M4 subtype, favorable-risk cytogenetics, and NPM1 mutation. Patients with GATA2 mutation had significantly better overall survival and relapse-free survival than those without GATA2 mutation. Sequential analysis showed that the original GATA2 mutations might be lost during disease progression in GATA2-mutated patients, while novel GATA2 mutations might be acquired at relapse in GATA2-wild patients. In conclusion, AML patients with GATA2 mutations had distinct clinic-biological features and a favorable prognosis. GATA2 mutations might be lost or acquired at disease progression, implying that it was a second hit in the leukemogenesis of AML, especially those with CEBPA mutation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Tsai FY, Keller G, Kuo FC, Weiss M, Chen J, Rosenblatt M, Alt FW, Orkin SH (1994) An early haematopoietic defect in mice lacking the transcription factor GATA-2. Nature 371(6494):221–226. doi:10.1038/371221a0

    Article  CAS  PubMed  Google Scholar 

  2. Tsai FY, Orkin SH (1997) Transcription factor GATA-2 is required for proliferation/survival of early hematopoietic cells and mast cell formation, but not for erythroid and myeloid terminal differentiation. Blood 89(10):3636–3643

    CAS  PubMed  Google Scholar 

  3. Hahn CN, Chong CE, Carmichael CL, Wilkins EJ, Brautigan PJ, Li XC, Babic M, Lin M, Carmagnac A, Lee YK, Kok CH, Gagliardi L, Friend KL, Ekert PG, Butcher CM, Brown AL, Lewis ID, To LB, Timms AE, Storek J, Moore S, Altree M, Escher R, Bardy PG, Suthers GK, D’Andrea RJ, Horwitz MS, Scott HS (2011) Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nat Genet 43(10):1012–1017. doi:10.1038/ng.913

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Zhang SJ, Ma LY, Huang QH, Li G, Gu BW, Gao XD, Shi JY, Wang YY, Gao L, Cai X, Ren RB, Zhu J, Chen Z, Chen SJ (2008) Gain-of-function mutation of GATA-2 in acute myeloid transformation of chronic myeloid leukemia. Proc Natl Acad Sci U S A 105(6):2076–2081. doi:10.1073/pnas.0711824105

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Greif PA, Dufour A, Konstandin NP, Ksienzyk B, Zellmeier E, Tizazu B, Sturm J, Benthaus T, Herold T, Yaghmaie M, Dorge P, Hopfner KP, Hauser A, Graf A, Krebs S, Blum H, Kakadia PM, Schneider S, Hoster E, Schneider F, Stanulla M, Braess J, Sauerland MC, Berdel WE, Buchner T, Woermann BJ, Hiddemann W, Spiekermann K, Bohlander SK (2012) GATA2 zinc finger 1 mutations associated with biallelic CEBPA mutations define a unique genetic entity of acute myeloid leukemia. Blood 120(2):395–403. doi:10.1182/blood-2012-01-403220

    Article  CAS  PubMed  Google Scholar 

  6. Fasan A, Eder C, Haferlach C, Grossmann V, Kohlmann A, Dicker F, Kern W, Haferlach T, Schnittger S (2013) GATA2 mutations are frequent in intermediate-risk karyotype AML with biallelic CEBPA mutations and are associated with favorable prognosis. Leukemia 27(2):482–485. doi:10.1038/leu.2012.174

    Article  CAS  PubMed  Google Scholar 

  7. Green CL, Tawana K, Hills RK, Bodor C, Fitzgibbon J, Inglott S, Ancliff P, Burnett AK, Linch DC, Gale RE (2013) GATA2 mutations in sporadic and familial acute myeloid leukaemia patients with CEBPA mutations. Br J Haematol 161(5):701–705. doi:10.1111/bjh.12317

    Article  CAS  PubMed  Google Scholar 

  8. Yan XJ, Xu J, Gu ZH, Pan CM, Lu G, Shen Y, Shi JY, Zhu YM, Tang L, Zhang XW, Liang WX, Mi JQ, Song HD, Li KQ, Chen Z, Chen SJ (2011) Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat Genet 43(4):309–315. doi:10.1038/ng.788

    Article  CAS  PubMed  Google Scholar 

  9. Shiba N, Funato M, Ohki K, Park MJ, Mizushima Y, Adachi S, Kobayashi M, Kinoshita A, Sotomatsu M, Arakawa H, Tawa A, Horibe K, Tsukimoto I, Hayashi Y (2013) Mutations of the GATA2 and CEBPA genes in paediatric acute myeloid leukaemia. Br J Haematol. doi:10.1111/bjh.12559

    Google Scholar 

  10. Hou HA, Kuo YY, Liu CY, Chou WC, Lee MC, Chen CY, Lin LI, Tseng MH, Huang CF, Chiang YC, Lee FY, Liu MC, Liu CW, Tang JL, Yao M, Huang SY, Ko BS, Hsu SC, Wu SJ, Tsay W, Chen YC, Tien HF (2012) DNMT3A mutations in acute myeloid leukemia: stability during disease evolution and clinical implications. Blood 119(2):559–568. doi:10.1182/blood-2011-07-369934

    Article  CAS  PubMed  Google Scholar 

  11. Hou HA, Lin CC, Chou WC, Liu CY, Chen CY, Tang JL, Lai YJ, Tseng MH, Huang CF, Chiang YC, Lee FY, Kuo YY, Lee MC, Liu MC, Liu CW, Lin LI, Yao M, Huang SY, Ko BS, Hsu SC, Wu SJ, Tsay W, Chen YC, Tien HF (2014) Integration of cytogenetic and molecular alterations in risk stratification of 318 patients with de novo non-M3 acute myeloid leukemia. Leukemia 28(1):50–58. doi:10.1038/leu.2013.236

    Article  CAS  PubMed  Google Scholar 

  12. Tien HF, Wang CH, Lin MT, Lee FY, Liu MC, Chuang SM, Chen YC, Shen MC, Lin KH, Lin DT (1995) Correlation of cytogenetic results with immunophenotype, genotype, clinical features, and ras mutation in acute myeloid leukemia. A study of 235 Chinese patients in Taiwan. Cancer Genet Cytogenet 84(1):60–68

    Article  CAS  PubMed  Google Scholar 

  13. Tang JL, Hou HA, Chen CY, Liu CY, Chou WC, Tseng MH, Huang CF, Lee FY, Liu MC, Yao M, Huang SY, Ko BS, Hsu SC, Wu SJ, Tsay W, Chen YC, Lin LI, Tien HF (2009) AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations. Blood 114(26):5352–5361. doi:10.1182/blood-2009-05-223784

    Article  CAS  PubMed  Google Scholar 

  14. Chou WC, Tang JL, Lin LI, Yao M, Tsay W, Chen CY, Wu SJ, Huang CF, Chiou RJ, Tseng MH, Lin DT, Lin KH, Chen YC, Tien HF (2006) Nucleophosmin mutations in de novo acute myeloid leukemia: the age-dependent incidences and the stability during disease evolution. Cancer Res 66(6):3310–3316

    Article  CAS  PubMed  Google Scholar 

  15. Chen CY, Lin LI, Tang JL, Tsay W, Chang HH, Yeh YC, Huang CF, Chiou RJ, Yao M, Ko BS, Chen YC, Lin KH, Lin DT, Tien HF (2006) Acquisition of JAK2, PTPN11, and RAS mutations during disease progression in primary myelodysplastic syndrome. Leukemia 20(6):1155–1158

    Article  PubMed  Google Scholar 

  16. Chen CY, Lin LI, Tang JL, Ko BS, Tsay W, Chou WC, Yao M, Wu SJ, Tseng MH, Tien HF (2007) RUNX1 gene mutation in primary myelodysplastic syndrome–the mutation can be detected early at diagnosis or acquired during disease progression and is associated with poor outcome. Br J Haematol 139(3):405–414. doi:10.1111/j.1365-2141.2007.06811.x

    Article  CAS  PubMed  Google Scholar 

  17. Hou HA, Chou WC, Lin LI, Chen CY, Tang JL, Tseng MH, Huang CF, Chiou RJ, Lee FY, Liu MC, Tien HF (2008) Characterization of acute myeloid leukemia with PTPN11 mutation: the mutation is closely associated with NPM1 mutation but inversely related to FLT3/ITD. Leukemia 22(5):1075–1078. doi:10.1038/sj.leu.2405005

    Article  CAS  PubMed  Google Scholar 

  18. Lin LI, Chen CY, Lin DT, Tsay W, Tang JL, Yeh YC, Shen HL, Su FH, Yao M, Huang SY, Tien HF (2005) Characterization of CEBPA mutations in acute myeloid leukemia: most patients with CEBPA mutations have biallelic mutations and show a distinct immunophenotype of the leukemic cells. Clin Cancer Res 11(4):1372–1379

    Article  CAS  PubMed  Google Scholar 

  19. Falini B, Mecucci C, Tiacci E, Alcalay M, Rosati R, Pasqualucci L, La Starza R, Diverio D, Colombo E, Santucci A, Bigerna B, Pacini R, Pucciarini A, Liso A, Vignetti M, Fazi P, Meani N, Pettirossi V, Saglio G, Mandelli F, Lo-Coco F, Pelicci PG, Martelli MF (2005) Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 352(3):254–266

    Article  CAS  PubMed  Google Scholar 

  20. Hou HA, Huang TC, Lin LI, Liu CY, Chen CY, Chou WC, Tang JL, Tseng MH, Huang CF, Chiang YC, Lee FY, Liu MC, Yao M, Huang SY, Ko BS, Hsu SC, Wu SJ, Tsay W, Chen YC, Tien HF (2010) WT1 mutation in 470 adult patients with acute myeloid leukemia: stability during disease evolution and implication of its incorporation into a survival scoring system. Blood 115(25):5222–5231. doi:10.1182/blood-2009-12-259390

    Article  CAS  PubMed  Google Scholar 

  21. Shiah HS, Kuo YY, Tang JL, Huang SY, Yao M, Tsay W, Chen YC, Wang CH, Shen MC, Lin DT, Lin KH, Tien HF (2002) Clinical and biological implications of partial tandem duplication of the MLL gene in acute myeloid leukemia without chromosomal abnormalities at 11q23. Leukemia 16(2):196–202

    Article  CAS  PubMed  Google Scholar 

  22. Chen TC, Hou HA, Chou WC, Tang JL, Kuo YY, Chen CY, Tseng MH, Huang CF, Lai YJ, Chiang YC, Lee FY, Liu MC, Liu CW, Liu CY, Yao M, Huang SY, Ko BS, Hsu SC, Wu SJ, Tsay W, Chen YC, Tien HF (2014) Dynamics of ASXL1 mutation and other associated genetic alterations during disease progression in patients with primary myelodysplastic syndrome. Blood Cancer J 4:e177. doi:10.1038/bcj.2013.74

    Article  PubMed Central  PubMed  Google Scholar 

  23. Lin CC, Hou HA, Chou WC, Kuo YY, Liu CY, Chen CY, Lai YJ, Tseng MH, Huang CF, Chiang YC, Lee FY, Liu MC, Liu CW, Tang JL, Yao M, Huang SY, Ko BS, Wu SJ, Tsay W, Chen YC, Tien HF (2013) IDH mutations are closely associated with mutations of DNMT3A, ASXL1 and SRSF2 in patients with myelodysplastic syndromes and are stable during disease evolution. Am J Hematol. doi:10.1002/ajh.23596

    Google Scholar 

  24. Chou WC, Lei WC, Ko BS, Hou HA, Chen CY, Tang JL, Yao M, Tsay W, Wu SJ, Huang SY, Hsu SC, Chen YC, Chang YC, Kuo KT, Lee FY, Liu MC, Liu CW, Tseng MH, Huang CF, Tien HF (2011) The prognostic impact and stability of Isocitrate dehydrogenase 2 mutation in adult patients with acute myeloid leukemia. Leukemia 25(2):246–253. doi:10.1038/leu.2010.267

    Article  CAS  PubMed  Google Scholar 

  25. Chou WC, Chou SC, Liu CY, Chen CY, Hou HA, Kuo YY, Lee MC, Ko BS, Tang JL, Yao M, Tsay W, Wu SJ, Huang SY, Hsu SC, Chen YC, Chang YC, Kuo KT, Lee FY, Liu MC, Liu CW, Tseng MH, Huang CF, Tien HF (2011) TET2 mutation is an unfavorable prognostic factor in acute myeloid leukemia patients with intermediate-risk cytogenetics. Blood. doi:10.1182/blood-2011-02-339747

    Google Scholar 

  26. Hou HA, Kuo YY, Tang JL, Chou WC, Yao M, Lai YJ, Lin CC, Chen CY, Liu CY, Tseng MH, Huang CF, Chiang YC, Lee FY, Liu MC, Liu CW, Huang SY, Ko BS, Wu SJ, Tsay W, Chen YC, Tien HF (2013) Clinical implications of the SETBP1 mutation in patients with primary myelodysplastic syndrome and its stability during disease progression. Am J Hematol. doi:10.1002/ajh.23611

    Google Scholar 

  27. Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, Schiffer CA, Doehner H, Tallman MS, Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W, Larson RA, Lowenberg B, Sanz MA, Head DR, Ohno R, Bloomfield CD (2003) Revised recommendations of the international working group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol 21(24):4642–4649. doi:10.1200/JCO.2003.04.036

    Article  PubMed  Google Scholar 

  28. Meshinchi S, Arceci RJ (2007) Prognostic factors and risk-based therapy in pediatric acute myeloid leukemia. Oncologist 12(3):341–355. doi:10.1634/theoncologist.12-3-341

    Article  PubMed  Google Scholar 

  29. von Neuhoff C, Reinhardt D, Sander A, Zimmermann M, Bradtke J, Betts DR, Zemanova Z, Stary J, Bourquin JP, Haas OA, Dworzak MN, Creutzig U (2010) Prognostic impact of specific chromosomal aberrations in a large group of pediatric patients with acute myeloid leukemia treated uniformly according to trial AML-BFM 98. J Clin Oncol 28(16):2682–2689. doi:10.1200/JCO.2009.25.6321

    Article  Google Scholar 

  30. Chou WC, Huang HH, Hou HA, Chen CY, Tang JL, Yao M, Tsay W, Ko BS, Wu SJ, Huang SY, Hsu SC, Chen YC, Huang YN, Chang YC, Lee FY, Liu MC, Liu CW, Tseng MH, Huang CF, Tien HF (2010) Distinct clinical and biological features of de novo acute myeloid leukemia with additional sex comb-like 1 (ASXL1) mutations. Blood 116(20):4086–4094. doi:10.1182/blood-2010-05-283291

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was partially sponsored by grants NSC 100-2314-B002-057-MY3, NSC 100-2314-B-002-112-MY3, and NSC 100–2628-B-002-003-MY3 from the National Science Council (Taiwan), MOHW103-TD-B-111-04 from the Ministry of Health and Welfare (Taiwan), and NTUH 102P06 and UN 102–015 from the Department of Medical Research, National Taiwan University Hospital.

Authorship

H.-A.H. was responsible for study design and plan, literature collection, data management and interpretation, statistical analysis, and manuscript writing. Y.-C.L was responsible for literature collection, data interpretation, and manuscript writing. C.-Y.L was responsible for statistical analysis and interpretation of the statistical findings. L.-I.L. and Y.-Y.K. were responsible for mutation analysis and interpretation. C.-C.L., C.-Y.C., W.-C.C., M.-Y., S.-Y.H., J.-L.T., B.-S.K., S.-C.H., S.-J.W., W.T., and Y.-C.C. contributed patient samples and clinical data. M.-H.T., C.-F.H., Y.-C.C., C.-W.L., and M.-C.L. performed the gene mutation and chromosomal studies. H.-F.T. planned, designed, and wrote the manuscript and coordinated the study over the entire period.

Conflict of interest

The authors declare no competing financial interests.

Author information

Authors and Affiliations

  1. Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

    Hsin-An Hou, Yun-Chu Lin, Wen-Chien Chou, Chien-Chin Lin, Chien-Yuan Chen, Mei-Hsuan Tseng, Chi-Fei Huang, Ying-Chieh Chiang, Jih-Luh Tang, Ming Yao, Shang-Yi Huang, Bor-Sheng Ko, Shang-Ju Wu, Woei Tsay, Yao-Chang Chen & Hwei-Fang Tien

  2. Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan

    Yuan-Yeh Kuo

  3. Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan

    Wen-Chien Chou, Chien-Chin Lin, Szu-Chun Hsu & Yao-Chang Chen

  4. Biostatistics Consulting Laboratory, Department of Nursing, National Taipei College of Nursing, Taipei, Taiwan

    Chieh-Yu Liu

  5. Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan

    Liang-In Lin

  6. Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan

    Ming-Chih Liu & Chia-Wen Liu

Authors
  1. Hsin-An Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yun-Chu Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuan-Yeh Kuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wen-Chien Chou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chien-Chin Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chieh-Yu Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chien-Yuan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Liang-In Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mei-Hsuan Tseng
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Chi-Fei Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ying-Chieh Chiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ming-Chih Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Chia-Wen Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Jih-Luh Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Ming Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Shang-Yi Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Bor-Sheng Ko
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Szu-Chun Hsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Shang-Ju Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Woei Tsay
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Yao-Chang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Hwei-Fang Tien
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hwei-Fang Tien.

Additional information

HA Hou and YC Lin contributed equally to this work

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Table 1

(DOCX 13 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hou, HA., Lin, YC., Kuo, YY. et al. GATA2 mutations in patients with acute myeloid leukemia-paired samples analyses show that the mutation is unstable during disease evolution. Ann Hematol 94, 211–221 (2015). https://doi.org/10.1007/s00277-014-2208-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-014-2208-8

Keywords

Search

Navigation