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Originally published as JCO Early Release 10.1200/JCO.2008.21.5418 on March 9 2009 © 2009 American Society of Clinical Oncology.
Role of CEBPA in Normal Karyotype Acute Myeloid LeukemiaDepartment of Medicine – Hematology, Stanford University School of Medicine, Stanford, CA To the Editor: Normal karyotype acute myeloid leukemia (NK-AML) is a molecularly heterogeneous disease.1,2 Several distinct molecular markers, such as FLT3 internal tandem duplication (FLT3-ITD), FLT3–tyrosine kinase domain (FLT3-TKD) point mutations, and mutations in NPM1 and WT1, have been reported to impact the treatment outcomes of patients age younger than 60 years with NK-AML.1,2 Based on these markers, patients can be molecularly stratified into two distinct groups. Patients with FLT3-ITD positive and/or NPM1 wild type are considered to have high-risk NK-AML, whereas patients with FLT3-ITD–negative and NPM1-mutated genotype have low-risk disease.1,3 Recently, Marcucci et al4 added CEBPA mutations to the list of molecularly significant prognostic markers in NK-AML. In their article, the authors demonstrated that CEBPA mutations cluster primarily in patients with molecular high-risk NK-AML, and its presence predicts for an improved event-free, disease-free, and overall survival.4 There are two distinct issues I believe deserve further clarification. The first issue relates to an abstract recently presented at the 2008 American Society of Hematology meeting. In their work, Wouters et al5 demonstrated that mutational deactivation of both CEBPA genes is associated with a distinct transcriptional signature, and only patients with double mutations in CEBPA are found to have improved clinical outcomes (event-free and overall survival). Although intriguing, these data certainly require confirmation by an independent data set. The second and clearly more pressing issue relates to the impact of CEBPA mutations in patients with molecularly high-risk NK-AML. Although the negative prognostic impact on clinical outcomes of patients with molecularly high-risk disease has been validated in several independent datasets,1,3,6 patients in this high-risk group are clearly not molecularly homogenous (FLT3-ITD positive v FLT3-ITD negative and NPM1 wild type). In fact, only nine of 32 patients in the CEBPA mutated group had a mutation in FLT3 (FLT3-ITD or FLT3-TKD), and 14 of 32 patients in that same cohort appeared to have no detectable mutational abnormality other than CEBPA. Given that FLT3-ITD was not an independent predictor of event-free survival in the molecularly high-risk group, it may, therefore, be interesting to differentially report the 5-year event-free and potentially disease-free and overall survival for patients in the high-risk cohort (FLT3-ITD positive v FLT3-ITD negative and NPM1 wild type), as it would be clinically relevant to understand if CEBPA mutations predicted improved outcomes primarily in the FLT3-ITD–negative and NPM1–wild-type cohort or whether it also impacted positively the poor prognosis with FLT3-ITD–positive NK-AML. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Schlenk RF, Döhner K, Krauter J, et al: Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 358:1909–1918, 2008. 2. Döhner K, Schlenk RF, Habdank M, et al: Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: Interaction with other gene mutations. Blood 106:3740–3746, 2005. 3. Paschka P, Marcucci G, Ruppert AS, et al: Wilms' tumor 1 gene mutations independently predict poor outcome in adults with cytogenetically normal acute myeloid leukemia: A Cancer and Leukemia Group B study. J Clin Oncol 26:4595–4602, 2008. 4. Marcucci G, Maharry K, Radmacher MD, et al: Prognostic significance of, and gene and microRNA expression signatures associated with, CEBPA mutations in cytogenetically normal acute myeloid leukemia with high-risk molecular features: A Cancer and Leukemia Group B study. J Clin Oncol 26:5078–5087, 2008. 5. Wouters BJ, Erpelinck-Verschueren CAJ, Lowenberg B, et al. Double, but not single, CEBPA mutations define a subgroup of acute myeloid leukemia with favorable outcome and a distinct gene expression profile blood ASH Annual Meeting Abstracts, 112 2008 p.141, abstr 8012. 6. Gale RE, Green C, Allen C, et al: The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood 111:2776–2784, 2008.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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