본문 바로가기
KERD
논문KCI 등재

Clinical Significance of bZIP In-Frame CEBPA-Mutated Normal Karyotype Acute Myeloid Leukemia

손상균|김성현|김희제|김형준|정철원|김미연|장준호|문준호|원종호|김미희|김태형|이제중|김동환|안재숙|송가영|정성훈|양덕환|안서연
대한암학회 (Korean Cancer Association)|2023.07|Cancer Research and Treatment|제55권 제3호|pp. 1011-1022|DOI 10.4143/crt.2022.1407

2

조회

0

다운로드

0

인용

0

참고문헌

키워드

LeukemiaAcuteNext-generation sequencingCEBPAMyeloidAllogeneic transplantation
주제분류의학일반

초록

Purpose We evaluated the characteristics of CCAAT/enhancer-binding protein α (CEBPA) mutations and the significance of a basic leucine zipper in-frame mutation (bZIPin-f) of CEBPA in patients with acute myeloid leukemia with a normal karyotype. Materials and Methods Based on updated knowledge of CEBPA mutations, we conducted next-generation sequencing analyses in a previously established real-world cohort. Results Among 78 of a total of 395 patients (19.7%), 50 had bZIPin-f CEBPA, and 28 had non-bZIPin-f CEBPA. In the multivariate analysis, patients with NPM1mut, those with bZIPin-f CEBPA, and those who underwent allogeneic hematopoietic cell transplantation (allo-HCT) had favorable overall survival (OS), but FLT3-ITDmut was a poor prognostic indicator. For relapse-free survival (RFS) and cumulative incidence of relapse, bZIPin-f CEBPA, and allo-HCT were associated with favorable outcomes; FLT3-ITDpos was associated with worse outcomes. In the CEBPA double-mutated group (CEBPAdm), bZIPin-f CEBPA was associated with superior outcomes in terms of OS (p=0.007) and RFS (p=0.007) compared with non-bZIPin-f CEBPA. Of 50 patients with bZIPin-f CEBPA, 36 patients had at least one mutation. When grouped by the presence of mutations in chromatic/DNA modifiers (C), cohesion complex (C), and splicing genes (S) (CCS mutations), CCS-mutated bZIPin-f CEBPA was associated with poor OS (p=0.044; hazard ratio [HR], 2.419) and a trend in inferior RFS (p=0.186; HR, 1.838). Conclusion Only bZIPin-f CEBPA was associated with favorable outcomes in patients with CEBPAdm. However, some mutations accompanying bZIPin-f CEBPA showed inferior OS; thus, further studies with larger numbers of patients are required for clear conclusions of the significance of bZIPin-f CEBPA.

Abstract

Purpose We evaluated the characteristics of CCAAT/enhancer-binding protein α (CEBPA) mutations and the significance of a basic leucine zipper in-frame mutation (bZIPin-f) of CEBPA in patients with acute myeloid leukemia with a normal karyotype. Materials and Methods Based on updated knowledge of CEBPA mutations, we conducted next-generation sequencing analyses in a previously established real-world cohort. Results Among 78 of a total of 395 patients (19.7%), 50 had bZIPin-f CEBPA, and 28 had non-bZIPin-f CEBPA. In the multivariate analysis, patients with NPM1mut, those with bZIPin-f CEBPA, and those who underwent allogeneic hematopoietic cell transplantation (allo-HCT) had favorable overall survival (OS), but FLT3-ITDmut was a poor prognostic indicator. For relapse-free survival (RFS) and cumulative incidence of relapse, bZIPin-f CEBPA, and allo-HCT were associated with favorable outcomes; FLT3-ITDpos was associated with worse outcomes. In the CEBPA double-mutated group (CEBPAdm), bZIPin-f CEBPA was associated with superior outcomes in terms of OS (p=0.007) and RFS (p=0.007) compared with non-bZIPin-f CEBPA. Of 50 patients with bZIPin-f CEBPA, 36 patients had at least one mutation. When grouped by the presence of mutations in chromatic/DNA modifiers (C), cohesion complex (C), and splicing genes (S) (CCS mutations), CCS-mutated bZIPin-f CEBPA was associated with poor OS (p=0.044; hazard ratio [HR], 2.419) and a trend in inferior RFS (p=0.186; HR, 1.838). Conclusion Only bZIPin-f CEBPA was associated with favorable outcomes in patients with CEBPAdm. However, some mutations accompanying bZIPin-f CEBPA showed inferior OS; thus, further studies with larger numbers of patients are required for clear conclusions of the significance of bZIPin-f CEBPA.

참고문헌 (23)

  1. Koschmieder S, "Dysregulation of the C", EBPalpha differentiation pathway in human cancer, 2009, pp.27, 619~628
  2. Martelli MP, "Mutational landscape of AML with normal cytogenetics : biological and clinical implications", Blood Rev, 27, pp.13~22 (2013)
  3. Pabst T, "Dominant-negative mutations of CEBPA, encoding CCAAT", enhancer binding protein-alpha(C, Nat Genet, pp.2001, 27[DOI]
  4. Green CL, "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, 28, pp.2739~2747 (2010)
  5. Schlenk RF, "The value of allogeneic and autologous hematopoietic stem cell transplantation in prognostically favorable acute myeloid leukemia with double mutant CEBPA", Blood, 122, pp.1576~1582 (2013)
  6. Fasan A, "The role of different genetic subtypes of CEBPA mutated AML", Leukemia, 28, pp.794~803 (2014)
  7. Park SH, "CEBPA single mutation can be a possible favorable prognostic indicator in NPM1 and FLT3-ITD wild-type acute myeloid leukemia patients with intermediate cytogenetic risk", Leuk Res, 37, pp.1488~1494 (2013)
  8. Swerdlow SH, "WHO classification of tumours of haematopoietic and lymphoid tissues" (2008), International Agency for Research on Cancer
  9. 황상미, "Classification of acute myeloid leukemia", Blood Research, 55, pp.1~4 (2020), 대한혈액학회[DOI]
  10. Schlenk RF, "Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia", N Engl J Med, 358, pp.1909~1918 (2008)
  11. Wouters BJ, "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, 113, pp.3088~3091 (2009)
  12. Li HY, "Favorable prognosis of biallelic CEBPA gene mutations in acute myeloid leukemia patients : a meta-analysis", Eur J Haematol, 94, pp.439~448 (2015)
  13. Ahn JS, "Normal karyotype acute myeloid leukemia patients with CEBPA double mutation have a favorable prognosis but no survival benefit from allogeneic stem cell transplant", Ann Hematol, 95, pp.301~310 (2016)
  14. Tarlock K, "CEBPA-bZip mutations are associated with favorable prognosis in de novo AML : a report from the Children’s Oncology Group", Blood, 138, pp.1137~1147 (2021)
  15. Wakita S, "Prognostic impact of CEBPA bZIP domain mutation in acute myeloid leukemia", Blood Adv, 6, pp.238~247 (2022)
  16. Taube F, "CEBPA mutations in 4708 patients with acute myeloid leukemia : differential impact of bZIP and TAD mutations on outcome", Blood, 139, pp.87~103 (2022)
  17. Dohner H, "Diagnosis and management of AML in adults : 2022 recommendations from an international expert panel on behalf of the ELN", Blood, 140, pp.1345~1377 (2022)
  18. Ahn JS, "Assessment of a new genomic classification system in acute myeloid leukemia with a normal karyotype", Oncotarget, 9, pp.4961~4968 (2018)
  19. Dohner H, "Diagnosis and management of AML in adults : 2017 ELN recommendations from an international expert panel", Blood, 129, pp.424~447 (2017)
  20. Kanda Y, "Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics", Bone Marrow Transplant, 48, pp.452~458 (2013)
  21. Su L, "Acute myeloid leukemia with CEBPA mutations : current progress and future directions", Front Oncol, 12, pp.806137~ (2022)
  22. Su L, "Mutational spectrum of acute myeloid leukemia patients with double CEBPA mutations based on next-generation sequencing and its prognostic significance", Oncotarget, 9, pp.24970~24979 (2018)
  23. Konstandin NP, "Genetic heterogeneity of cytogenetically normal AML with mutations of CEBPA", Blood Adv, 2, pp.2724~2731 (2018)

관련 논문AI추천

Novel Mutations in CEBPA in Korean Patients with Acute Myeloid Leukemia with a Normal Karyotype기창석, 김동환, 김선희, 김솔잎, 김종원, 김희진, 장미애, 장준호, 정철원대한진단검사의학회 · Annals of Laboratory Medicine2012 · 제32권 제2호Incidences and Prognostic Impact of c-KIT, WT1, CEBPA, and CBL Mutations, and Mutations Associated With Epigenetic Modification in Core Binding Factor Acute Myeloid Leukemia: A Multicenter Study in a Korean PopulationEun Yup Lee, Hawk Kim, Ho Jin Shin, Hyeoung-Joon Kim, Hyun Ji Lee, In-Suk Kim, Jeong-Eun Kang, Jong-Ho Won, Joo Seop Chung, Moo-Kon Song, Sang Hyuk Park, Soo-Mee Bang, Yeo-Kyeoung Kim대한진단검사의학회 · Annals of Laboratory Medicine2015 · 제35권 제3호급성골수성백혈병의 차세대 염기서열 분석을 통한 분자유전학적 위험도 분류안재숙대한내과학회 · 대한내과학회지2021 · 제96권 제6호Correlation of NPM1 Type A Mutation Burden With Clinical Status and Outcomes in Acute Myeloid Leukemia Patients With Mutated NPM1 Type A김인숙, 김형회, 박상혁, 박찬정, 이은엽, 이종윤, 장성수, 장철훈, 조수연, 조영욱, 지현숙대한진단검사의학회 · Annals of Laboratory Medicine2016 · 제36권 제5호Identification of Two Novel NPM1 Mutations in Patients with Acute Myeloid Leukemia김소연, 라은경, 박선양, 박성섭, 박승만, 서상원, 성문우, 전용범대한진단검사의학회 · Annals of Laboratory Medicine2013 · 제33권 제1호Reclassification of Acute Myeloid Leukemia According to the 2016 WHO Classification정진, 조빈, 김명신, 김용구, 김희제, 이재욱, 장우리, 정낙균, 조병식, 한경자, 한은희대한진단검사의학회 · Annals of Laboratory Medicine2019 · 제39권 제3호

이 간행물의 다른 논문 (32건)

Metastasis-Directed Local Therapy of Hepatic Oligometastasis from Colorectal Cancer and Future Perspective in Radiation Therapy조원경, 안용찬, 엄준원, 이종훈, 정재욱, 임채홍, 조현민, 유규상, 지의규pp. 707-719Cellular Dormancy in Cancer - Mechanisms and Potential Targeting Strategies이호영, 민혜영pp. 720-736Identification of Genes Involved in EGF-Induced Apoptosis Using CRISPR/Cas9 Knockout Screening: Implications for Novel Therapeutic Targets in EGFR-Overexpressing Cancers이주호, 전승혁, 김용섭, 전상록, 김재식, 우홍균pp. 737-745Immunogenicity and Safety of Vaccines Against Coronavirus Disease in Actively Treated Patients with Solid Tumors: A Prospective Cohort Study이충근, 박소라, 김규현, 안진영, 이연정, 염준섭, 정민규, 라선영, 김신영, 신상준, 김정호, 이경화, 정수진, 최준용, 구남수, 범승훈, 백예지pp. 746-757Recent Trends of Medical Expenses Associated with Radiation Therapy in Korea Based on HIRA Big Data허승재, 박원, 안용찬, 양경미, 이정은pp. 758-765
원문 보기