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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.

Authors :
Marcucci G
Maharry K
Radmacher MD
Mrózek K
Vukosavljevic T
Paschka P
Whitman SP
Langer C
Baldus CD
Liu CG
Ruppert AS
Powell BL
Carroll AJ
Caligiuri MA
Kolitz JE
Larson RA
Bloomfield CD
Source :
Journal of clinical oncology : official journal of the American Society of Clinical Oncology [J Clin Oncol] 2008 Nov 01; Vol. 26 (31), pp. 5078-87. Date of Electronic Publication: 2008 Sep 22.
Publication Year :
2008

Abstract

Purpose: To evaluate the prognostic significance of CEBPA mutations in the context of established molecular markers in cytogenetically normal (CN) acute myeloid leukemia (AML) and gain biologic insights into leukemogenesis of the CN-AML molecular high-risk subset (FLT3 internal tandem duplication [ITD] positive and/or NPM1 wild type) that has a significantly higher incidence of CEBPA mutations than the molecular low-risk subset (FLT3-ITD negative and NPM1 mutated).<br />Patients and Methods: One hundred seventy-five adults age less than 60 years with untreated primary CN-AML were screened before treatment for CEBPA, FLT3, MLL, WT1, and NPM1 mutations and BAALC and ERG expression levels. Gene and microRNA (miRNA) expression profiles were obtained for the CN-AML molecular high-risk patients.<br />Results: CEBPA mutations predicted better event-free (P = .007), disease-free (P = .014), and overall survival (P < .001) independently of other molecular and clinical prognosticators. Among patients with CEBPA mutations, 91% were in the CN-AML molecular high-risk group. Within this group, CEBPA mutations predicted better event-free (P < .001), disease-free (P = .004), and overall survival (P = .009) independently of other molecular and clinical characteristics and were associated with unique gene and miRNA expression profiles. The major features of these profiles were upregulation of genes (eg, GATA1, ZFPM1, EPOR, and GFI1B) and miRNAs (ie, the miR-181 family) involved in erythroid differentiation and downregulation of homeobox genes.<br />Conclusion: Pretreatment testing for CEBPA mutations identifies CN-AML patients with different outcomes, particularly in the molecular high-risk group, thus improving molecular risk-based classification of this large cytogenetic subset of AML. The gene and miRNA expression profiling provided insights into leukemogenesis of the CN-AML molecular high-risk group, indicating that CEBPA mutations are associated with partial erythroid differentiation.

Details

Language :
English
ISSN :
1527-7755
Volume :
26
Issue :
31
Database :
MEDLINE
Journal :
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Publication Type :
Academic Journal
Accession number :
18809607
Full Text :
https://doi.org/10.1200/JCO.2008.17.5554