Annals of Hematology

, Volume 92, Issue 2, pp 163–171 | Cite as

KIT D816 mutation associates with adverse outcomes in core binding factor acute myeloid leukemia, especially in the subgroup with RUNX1/RUNX1T1 rearrangement

  • Hee-Jin Kim
  • Hee Kyung Ahn
  • Chul Won Jung
  • Joon Ho Moon
  • Chang-Hun Park
  • Ki-O Lee
  • Sun-Hee Kim
  • Yeo-Kyeoung Kim
  • Hyeoung-Joon Kim
  • Sang Kyun Sohn
  • Sung Hyun Kim
  • Won Sik Lee
  • Kyoung Ha Kim
  • Yeung-Chul Mun
  • Hawk Kim
  • Jinny Park
  • Woo-Sung Min
  • Hee-Je Kim
  • Dong Hwan Dennis Kim
  • on behalf of AML/MDS working party, Korean Society of Hematology
Original Article

Abstracts

Core binding factor (CBF)-positive acute myeloid leukemia (AML) presents a favorable prognosis, except for patients with KIT mutation, especially D816 mutation. The current retrospective study attempted to validate a prognostic role of KIT mutation in 121 Korean patients with CBF AML. The study patients consisted of 121 patients with CBF AML (82 patients with RUNX1/RUNX1T1 [67.8 %] and 39 patients with CBFB/MYH11 [32.2 %]) recruited from eight institutions in Korea. All patients received idarubicin plus cytarabine or behenoyl cytosine arabinoside 3 + 7 induction chemotherapy. The KIT gene mutation status was determined by direct sequencing analyses. A KIT mutation was detected in 32 cases (26.4 %) in our series of patients. The KIT mutation was most frequent in exon 17 (n = 18, 14.9 %; n = 16 with D816 mutation), followed by exon 8 (n = 10, 8.3 %). The presence of KIT D816 mutation was associated with adverse outcomes for the event-free survival (p = 0.03) and for the overall survival (p = 0.02). The unfavorable impact of D816 mutation was more prominent when the analysis was confined to the RUNX1/RUNX1T1 subtype. The KIT mutation was detected in 26.4 % of Korean patients with CBF AML. The KIT D816 mutation demonstrated an unfavorable prognostic implication, particularly in the RUNX1/RUNX1T1 subtype.

Keywords

Core binding factor-positive acute myeloid leukemia KIT Mutation Korea 

Notes

Acknowledgments

This work was supported by the National Research Foundation of Korea(NRF) grant funded by the Korea government(MEST) (2009-0088130 and 2010-0028016), by a grant from the Korea Health 21 R&D Project, Ministry of Health & Welfare, Korea (01-PJ10-PG6-01GN16-0005) and by a grant #CRS-108-02-1 from the Clinical Research Development Program at Samsung Medical Center, Seoul, Korea. The biospecimens for this study were provided in part by the Chonnam National University Hwasun Hospital National Biobank of Korea, a member of the National Biobank of Korea, which is supported by the Ministry of Health, Welfare and Family Affairs. All samples derived from the National Biobank of Korea were obtained with informed consent under institutional review board-approved protocols.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

277_2012_1580_MOESM1_ESM.doc (40 kb)
ESM 1 (DOC 39 kb)

References

  1. 1.
    Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A, Paietta E, Willman CL, Head DR, Rowe JM, Forman SJ, Appelbaum FR (2000) Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 96:4075–4083PubMedGoogle Scholar
  2. 2.
    Erickson P, Gao J, Chang KS, Look T, Whisenant E, Raimondi S, Lasher R, Trujillo J, Rowley J, Drabkin H (1992) Identification of breakpoints in t(8;21) acute myelogenous leukemia and isolation of a fusion transcript, AML1/ETO, with similarity to Drosophila segmentation gene, runt. Blood 80:1825–1831PubMedGoogle Scholar
  3. 3.
    Liu P, Tarle SA, Hajra A, Claxton DF, Marlton P, Freedman M, Siciliano MJ, Collins FS (1993) Fusion between transcription factor CBF beta/PEBP2 beta and a myosin heavy chain in acute myeloid leukemia. Science 261:1041–1044PubMedCrossRefGoogle Scholar
  4. 4.
    Marcucci G, Mrozek K, Ruppert AS, Maharry K, Kolitz JE, Moore JO, Mayer RJ, Pettenati MJ, Powell BL, Edwards CG, Sterling LJ, Vardiman JW, Schiffer CA, Carroll AJ, Larson RA, Bloomfield CD (2005) Prognostic factors and outcome of core binding factor acute myeloid leukemia patients with t(8;21) differ from those of patients with inv(16): a Cancer and Leukemia Group B study. J Clin Oncol 23:5705–5717PubMedCrossRefGoogle Scholar
  5. 5.
    Schlenk RF, Benner A, Krauter J, Buchner T, Sauerland C, Ehninger G, Schaich M, Mohr B, Niederwieser D, Krahl R, Pasold R, Dohner K, Ganser A, Dohner H, Heil G (2004) Individual patient data-based meta-analysis of patients aged 16 to 60 years with core binding factor acute myeloid leukemia: a survey of the German Acute Myeloid Leukemia Intergroup. J Clin Oncol 22:3741–3750PubMedCrossRefGoogle Scholar
  6. 6.
    Boissel N, Leroy H, Brethon B, Philippe N, de Botton S, Auvrignon A, Raffoux E, Leblanc T, Thomas X, Hermine O, Quesnel B, Baruchel A, Leverger G, Dombret H, Preudhomme C (2006) Incidence and prognostic impact of c-Kit, FLT3, and Ras gene mutations in core binding factor acute myeloid leukemia (CBF-AML). Leukemia 20:965–970PubMedCrossRefGoogle Scholar
  7. 7.
    Care RS, Valk PJ, Goodeve AC, Abu-Duhier FM, Geertsma-Kleinekoort WM, Wilson GA, Gari MA, Peake IR, Lowenberg B, Reilly JT (2003) Incidence and prognosis of c-KIT and FLT3 mutations in core binding factor (CBF) acute myeloid leukaemias. Br J Haematol 121:775–777PubMedCrossRefGoogle Scholar
  8. 8.
    Cairoli R, Beghini A, Grillo G, Nadali G, Elice F, Ripamonti CB, Colapietro P, Nichelatti M, Pezzetti L, Lunghi M, Cuneo A, Viola A, Ferrara F, Lazzarino M, Rodeghiero F, Pizzolo G, Larizza L, Morra E (2006) Prognostic impact of c-KIT mutations in core binding factor leukemias: an Italian retrospective study. Blood 107:3463–3468PubMedCrossRefGoogle Scholar
  9. 9.
    Schnittger S, Kohl TM, Haferlach T, Kern W, Hiddemann W, Spiekermann K, Schoch C (2006) KIT-D816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival. Blood 107:1791–1799PubMedCrossRefGoogle Scholar
  10. 10.
    Shimada A, Taki T, Tabuchi K, Tawa A, Horibe K, Tsuchida M, Hanada R, Tsukimoto I, Hayashi Y (2006) KIT mutations, and not FLT3 internal tandem duplication, are strongly associated with a poor prognosis in pediatric acute myeloid leukemia with t(8;21): a study of the Japanese Childhood AML Cooperative Study Group. Blood 107:1806–1809PubMedCrossRefGoogle Scholar
  11. 11.
    Paschka P, Marcucci G, Ruppert AS, Mrozek K, Chen H, Kittles RA, Vukosavljevic T, Perrotti D, Vardiman JW, Carroll AJ, Kolitz JE, Larson RA, Bloomfield CD (2006) Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): a Cancer and Leukemia Group B Study. J Clin Oncol 24:3904–3911PubMedCrossRefGoogle Scholar
  12. 12.
    Luck SC, Russ AC, Du J, Gaidzik V, Schlenk RF, Pollack JR, Dohner K, Dohner H, Bullinger L (2010) KIT mutations confer a distinct gene expression signature in core binding factor leukaemia. Br J Haematol 148:925–937PubMedCrossRefGoogle Scholar
  13. 13.
    Lee DH, Chung NG, Cho B, Kim HK, Kang HJ, Shin HY, Ahn HS, Yoo KH, Sung KW, Koo HH, Kook H, Hwang TJ, Im HJ, Seo JJ, Park HJ (2010) Idarubicin plus behenoyl cytarabine and 6-thioguanine compares favorably with idarubicin plus cytarabine-based regimen for children with previously untreated acute myeloid leukemia: 10-year retrospective, multicenter study in Korea. J Korean Med Sci 25:9–15PubMedCrossRefGoogle Scholar
  14. 14.
    Mitelman F (1995) ISCN 1995: an International System for Human Cytogenetic Nomenclature (1995). Karger, BaselGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Hee-Jin Kim
    • 1
  • Hee Kyung Ahn
    • 2
  • Chul Won Jung
    • 2
  • Joon Ho Moon
    • 3
  • Chang-Hun Park
    • 1
  • Ki-O Lee
    • 4
  • Sun-Hee Kim
    • 1
  • Yeo-Kyeoung Kim
    • 5
  • Hyeoung-Joon Kim
    • 5
  • Sang Kyun Sohn
    • 3
  • Sung Hyun Kim
    • 6
  • Won Sik Lee
    • 7
  • Kyoung Ha Kim
    • 8
  • Yeung-Chul Mun
    • 9
  • Hawk Kim
    • 10
  • Jinny Park
    • 11
  • Woo-Sung Min
    • 12
  • Hee-Je Kim
    • 12
  • Dong Hwan Dennis Kim
    • 2
    • 13
  • on behalf of AML/MDS working party, Korean Society of Hematology
  1. 1.Department of Laboratory Medicine and Genetics, Samsung Medical CenterSungkyunkwan University School of MedicineSeoulSouth Korea
  2. 2.Division of Hematology–Oncology, Department of Medicine, Samsung Medical CenterSungkyunkwan University School of MedicineSeoulSouth Korea
  3. 3.Department of Hematology/Oncology, Kyungpook National University HospitalKyungpook National UniversityDaeguSouth Korea
  4. 4.Samsung Biomedical Research InstituteSamsung Medical CenterSeoulSouth Korea
  5. 5.Department of Hematology/Oncology, Chonnam National University Hwasun HospitalChonnam National UniversityHwasunSouth Korea
  6. 6.Department of Hematology/Oncology, DongA University Medical CenterDongA UniversityBusanSouth Korea
  7. 7.Department of Hematology/OncologyInje University Busan Paik HospitalBusanSouth Korea
  8. 8.Department of Hematology/OncologySoonchunhyang University Seoul HospitalSeoulSouth Korea
  9. 9.Department of Hematology/OncologyEwha Womans University School of MedicineSeoulSouth Korea
  10. 10.Department of Hematology/Oncology, Ulsan University HospitalUniversity of Ulsan College of MedicineUlsanSouth Korea
  11. 11.Department of Hematology/Oncology, Gachon University Gil HospitalGachon University of Medicine and Science School of MedicineIncheonSouth Korea
  12. 12.Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St. Mary’s HospitalThe Catholic University of KoreaSeoulSouth Korea
  13. 13.Department of Medical Oncology and Hematology, Princess Margaret HospitalUniversity of TorontoTorontoCanada

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