Cancer Research and Treatment

Original Articles

Hematologic malignancy

Clinical Significance of bZIP In-Frame CEBPA-Mutated Normal Karyotype Acute Myeloid Leukemia: Seo-Yeon Ahn, TaeHyung Kim, Mihee Kim, Ga-Young Song, Sung-Hoon Jung, Deok-Hwan Yang, Je-Jung Lee, Mi Yeon Kim, Chul Won Jung, Jun-Ho Jang, Hee Je Kim, Joon Ho Moon, Sang Kyun Sohn, Jong-Ho Won, Sung-Hyun Kim, Hyeoung-Joon Kim, Jae-Sook Ahn, Dennis Dong Hwan Kim; Cancer Res Treat. 2023;55(3):1011-1022. Published online January 26, 2023; DOI: https://doi.org/10.4143/crt.2022.1407

Purpose
We evaluated the characteristics of CCAAT/enhancer-binding protein α (CEBPA) mutations and the significance of a basic leucine zipper in-frame mutation (bZIP^in-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 bZIP^in-f CEBPA, and 28 had non-bZIP^in-f CEBPA. In the multivariate analysis, patients with NPM1^mut, those with bZIP^in-f CEBPA, and those who underwent allogeneic hematopoietic cell transplantation (allo-HCT) had favorable overall survival (OS), but FLT3-ITD^mut was a poor prognostic indicator. For relapse-free survival (RFS) and cumulative incidence of relapse, bZIP^in-f CEBPA, and allo-HCT were associated with favorable outcomes; FLT3-ITD^pos was associated with worse outcomes. In the CEBPA double-mutated group (CEBPA^dm), bZIP^in-f CEBPA was associated with superior outcomes in terms of OS (p=0.007) and RFS (p=0.007) compared with non-bZIP^in-f CEBPA. Of 50 patients with bZIP^in-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 bZIP^in-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 bZIP^in-f CEBPA was associated with favorable outcomes in patients with CEBPA^dm. However, some mutations accompanying bZIP^in-f CEBPA showed inferior OS; thus, further studies with larger numbers of patients are required for clear conclusions of the significance of bZIP^in-f CEBPA.

Citations

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Prognostic value of CEBPA bZIP signatures in cytogenetically normal acute myeloid leukaemia
Li‐Xin Wu, Ming‐Yue Liao, Ming‐Yue Zhao, Nan Yan, Ping Zhang, Li‐Xia Liu, Jia‐Yue Qin, Shan‐Bo Cao, Jia Feng, Qian Jiang, Ying‐Jun Chang, Lan‐Ping Xu, Xiao‐Hui Zhang, Xiao‐Jun Huang, Hao Jiang, Hong‐Yu Zhang, Guo‐Rui Ruan
British Journal of Haematology.2025;[Epub] CrossRef
CEBPA double mutations associated with ABO antigen weakness in hematologic diseases
Seung Jun Choi, Hyun Kyung Kim, Eun Jung Suh, Soon Sung Kwon, Saeam Shin, Seung-Tae Lee, Sinyoung Kim
Blood Advances.2024; 8(6): 1487. CrossRef
CEBPA bZIP in-frame mutations in acute myeloid leukemia: prognostic and therapeutic implications
Fenghong Zhang, Zhen Shen, Jundan Xie, Jingren Zhang, Qian Wu, Rui Jiang, Xiangyu Zhao, Xiaofei Yang, Suning Chen
Blood Cancer Journal.2024;[Epub] CrossRef
Mutations in the bZip region of the CEBPA gene: A novel prognostic factor in patients with acute myeloid leukemia
Juan Carlos Rivera, Daniel Nuñez, Elizabet Millar, Kimberly Ramirez, Mauricio Chandía, Claudio Aguayo
International Journal of Laboratory Hematology.2023; 45(6): 833. CrossRef

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Autologous or Allogeneic Bone Marrow Transplantation Compared with Consolidation Chemotherapy in Acute promyelocytic Leukemia: Chang Ki Min, Woo Sung Min, Hee Je Kim, Hyun Suk Eom, Jong Wook Lee, Kyungja Han, Ihl Bhong Choi, Chun Choo Kim, Won IL Kim, Dong Jip Kim; J Korean Cancer Assoc. 1999;31(2):331-338.

Abstract PDF: PURPOSE
Acute promyelocytic leukemia (APL) is a distinct subtype of acute myelogenous leukemia characterized by the morphology of blast cells (M3 in FAB classification), the t (15;17) translocation, and a coagulopathy combining disseminated intravascular coagulation and fibrinolysis. It has been considered to have better response to combination chemo- therapy of an anthracycline and cytosine arabinoside and a higher cure rate than other subtypes because of recent approach of differentiating leukemic blasts by all-transretinoic acid (ATRA). The role of stem cell transplantation in APL has to be determined in comparison with that of consolidation chemotherapy.
MATERIALS AND METHODS
We compared the leukemia-free survival and overall survival between APL patients receiving the consolidation chemotherapy and those undergoing the allogeneic or autologous stem cell transplantation following the high-dose anticancer therapy. Of the 65 patients achieving the first complete remission from 1992 to 1997, 33 patients were treated with 3 courses of consolidation chemotherapies and 32 with the stem cell transplantation.
RESULTS
With a median follow-up of 22 months (8-60), the actuarial leukemia-free survival at 3 years was significantly higher in transplantation group than in chematherapy group (73.8% versus 33.5%; P=0.0087), and the probability of leukemic relapse was considerably lower in transplantation group than in chemotherapy group (6.3% versus 57.5%; P=0.001). The treatment-related mortalities of the groups were 0% in chemotherapy group and 14.3% in transplantation group. The main cause of deaths was relapse in the consolidation chemotherapy group.
CONCLUSION
These data demonstrate that the stem cell transplantation results in better leukemia-free survival than the consolidation chemotherapy for patients with APL in the first complete remission because of lower risk of relapse.

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Expression of Multidrug Resistant Genes in Bone Marrow Mononuclear Cells of Patients with Myeloid Leukemia: Seok Goo Cho, Il Ho Yang, Hyeon Seok Eom, Chang Gi Min, Hee Je Kim, Dong Wook Kim, Jong Wook Lee, Chi Wha Han, Woo Sung Min, Won Il Kim, Chun Choo Kim; J Korean Cancer Assoc. 1999;31(1):153-164.

Abstract PDF: PURPOSE
Multidrug resistance mediated by several drug resistant genes impedes the successful outcome of anti-cancer chemotherapy. In this study, we investigated the expressions of drug resistant genes encoding multidrug resistance (MDR1), multidrug resistance-associated protein (MRP), topoisomerase I (Topo I), topoisomerase II g (Topo II a) in narmal volunteers (n=12) in and patients with myeloid leukemia (n=34). Material and Method: We compared the levels of their transcripts in bone matrow mononuclear cells by semiquantitative RT-PCR. The amount of specific transcripts was represented as the optical density ratio of PCR product of target gene to that of B2- microglobulin (MG). Twenty patients of acute myelogenous leukemia (eight in remission state, twelve in refractory) and fourteen patients of chronic myelogenous leukemia (nine in chronic phase and five in blastic crisis) were examined. Twelve normal healthy persons were compared with leukemic patients.
RESULTS
The expression levels of all resistant genes in normal volunteers were relatively high as those of AML patients. Regardless of the disease status including remission status of AML (complete remission versus refractory) and the phase of CML (chronic phase versus blastic phase), the expression levels of all resistant genes in patients with CML were significantly lower than in the patients with AML (p < 0.05). Of interest, the patients with refractary AML did not show any statistical difference in comparison with normal controls and even the patients with AML in complete remission. Among the four drug resistant genes, the optical density ratio of MDRl was significantly lower than that of any other genes (p<0.05). Using HL-60 cell line, we compared the changes of various resistant gene expressions before and after differentiation induced by dimethylsulfoxide. The expressions of resistant genes declined in paralle1 with granulocytic differentiation, suggesting that the induction of cell differentiation might make leukemic cells susceptible to chemotherapeutic agents.
CONCLUSION
It is impossibble to explain the mechanism of drug resistance by comparing the level of drug resistant gene expression between nonnal subjects and patients with myeloid leukemias. Therefore, we suppose that longitudinal study of drug resistant gene expression is necessary to demonstrate the development of drug resistant during chemotherapy.

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A Preliminary Report of Busulfan, Melphalan and Thiotepa or TBI-containing Bi-alkylator Chemotherapy as a Preparative Regimen for Allogeneic Bone Marrow Transplantation in Refractory or Relapsed Acute Leukemias: Hee Je Kim, Woo Sung Min, Sung Kyu Park, Dong Wook Kim, Jong Wook Lee, Chi Hwa Han, Chun Choo Kim, Dong Jip Kim; J Korean Cancer Assoc. 1997;29(5):874-885.

Abstract PDF: PURPOSE
We assessed the three-alkylator combination of busulfan, melphalan and thiotepa or TBI, melphalan and thiotepa conditioning for allogeneic stem cell transplantation in 7 adult patients with refractory or relapsed acute leukemias.
MATERIALS AND METHODS
Six patients were transplanted for acute myeloid leukemia, one for acute lymphoblastic leukemia and included 5 of relapsed refractory, 2 of relapsed after first-BMT. All but 1 cases received G-CSF stimulated CD34+ allogeneic peripheral blood progenitor cells (PBPCs) in addition to stimulated allogeneic marrow.
RESULTS
All patients except one engrafted (median time to ANC >0.5 10 (9)/L=11days, to platelets >30 X 10 (9)/L=14 days) successfully and complete remission was obtained in 6 patients. Grade I-II acute GVHD and controllable regimen-related toxicity especially oral mucositis (grade II-III) developed in all cases, but 2 patients including one second- allogeneic BMT patient expired early by transplant-related toxicity of hepatic or multiorgan failure along the course of sepsis.
CONCLUSION
Although the observation period on these cases are limited, the data presented show that the combination of busulfan, melphalan and thiotepa is tolerable as a preparative regimen for allogeneic marrow transplantation in high-risk leukemic patients. We think that these encouraging results need to be confirmed in prospective studies in the future.

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