Bienz Marianne, Ludwig Madleina, Leibundgut Elisabeth Oppliger, Mueller Beatrice U, Ratschiller Daniel, Solenthaler Max, Fey Martin F, Pabst Thomas
Institute of Medical Oncology and the Laboratory for Molecular Diagnostics, Department of Hematology, University of Berne, CH-3010 Berne, Switzerland.
Clin Cancer Res. 2005 Feb 15;11(4):1416-24. doi: 10.1158/1078-0432.CCR-04-1552.
The recognition of a number of leukemia-specific cytogenetic abnormalities and their role as independent prognostic factors have provided considerable insights into leukemia pathogenesis and have paved the way to adopt risk-adapted treatment. However, approximately 50% of newly diagnosed acute myeloid leukemia (AML) have a normal karyotype. There has therefore been much interest in identifying molecular markers that could help to improve the prognostic stratification of patients with normal-karyotype AML.
Consecutive untreated AML patients (n = 67) from a single institution all with normal karyotype were analyzed for the presence of mutations in the myeloid transcription factor gene CEBPA (for CCAAT/enhancer binding protein-alpha), for internal tandem duplications (ITD) of the tyrosine kinase receptor gene FLT3 (for fms-like tyrosine kinase 3), and for expression of the BAALC gene (for brain and acute leukemia, cytoplasmic).
17.9% of normal-karyotype AML had mutations in the CEBPA gene, and 28.4% had FLT3-ITD; 65.7% (44 of 67) had high BAALC expression and 34.3% (23 of 67) had low BAALC expression. Patients with CEBPA mutations had a very favorable course of their disease. Median disease-free survival (DFS) and overall survival (OS) were 33.5 and 45.5 months, respectively, compared with 10 (e.g., 12 months in patients without CEBPA mutations; P = 0.0017; P = 0.0007). AML patients with FLT3-ITD had significantly shorter median DFS (P = 0.0328) and OS (P = 0.0148) than patients without FLT3-ITD. High BAALC expression predicted for a shorter DFS (P = 0.0152) and OS (P = 0.0210) compared with AML with low BAALC expression; 53.7% of normal-karyotype AML had neither FLT3-ITD nor CEBPA mutations. We found that high BAALC expression in normal-karyotype AML with neither FLT3-ITD nor CEBPA mutations (18 of 67) indicates adverse prognosis for both DFS and OS (P = 0.0001; e.g., P = 0.0001) compared with the group with low BAALC expression and absent FLT3-ITD and CEBPA mutations (18 of 67). Thus, BAALC expression represents a novel prognostic marker particularly for normal-karyotype AML patients with neither FLT3-ITD nor CEBPA mutations.
Assessment of CEBPA mutations, FLT3-ITD, and BAALC expression permits to split normal-karyotype AML into clinically distinct subgroups.
对多种白血病特异性细胞遗传学异常及其作为独立预后因素的作用的认识，为白血病发病机制提供了相当多的见解，并为采用风险适应性治疗铺平了道路。然而，大约50%新诊断的急性髓系白血病（AML）患者核型正常。因此，人们对识别有助于改善核型正常的AML患者预后分层的分子标志物产生了浓厚兴趣。
对来自单一机构的67例未经治疗且核型均正常的连续AML患者进行分析，检测髓系转录因子基因CEBPA（CCAAT/增强子结合蛋白α）的突变情况、酪氨酸激酶受体基因FLT3（fms样酪氨酸激酶3）的内部串联重复（ITD）情况以及BAALC基因（脑和急性白血病，细胞质）的表达情况。
17.9%核型正常的AML患者CEBPA基因存在突变，28.4%存在FLT3-ITD；65.7%（67例中的44例）BAALC高表达，34.3%（67例中的23例）BAALC低表达。CEBPA基因突变的患者病程非常良好。无病生存期（DFS）和总生存期（OS）的中位数分别为33.5个月和45.5个月，而无CEBPA基因突变的患者分别为10个月（例如，12个月；P = 0.0017；P = 0.0007）。伴有FLT3-ITD的AML患者的DFS（P = 0.0328）和OS（P = 0.0148）中位数显著短于无FLT3-ITD的患者。与BAALC低表达的AML相比，BAALC高表达预示着DFS（P = 0.0152）和OS（P = 0.0210）更短；53.7%核型正常的AML既无FLT3-ITD也无CEBPA基因突变。我们发现，在既无FLT3-ITD也无CEBPA基因突变的核型正常的AML患者（67例中的18例）中，BAALC高表达表明DFS和OS预后不良（P = 0.0001；例如，P = 0.0001），而与BAALC低表达且无FLT3-ITD和CEBPA基因突变的组（67例中的18例）相比。因此，BAALC表达代表了一种新的预后标志物，尤其对于既无FLT3-ITD也无CEBPA基因突变的核型正常的AML患者。
对CEBPA突变、FLT3-ITD和BAALC表达的评估可将核型正常的AML分为临床特征不同的亚组。
Zotero 插件