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Dufour, A.* ; Schneider, F.* ; Metzeler, K.H.* ; Hoster, E.* ; Schneider, S.* ; Zellmeier, E.* ; Benthaus, T.* ; Sauerland, M.C.* ; Berdel, W.E.* ; Büchner, T.* ; Wörmann, B.* ; Braess, J.* ; Hiddemann, W. ; Bohlander, S.K. ; Spiekermann, K.

Acute myeloid leukemia with biallelic CEBPA gene mutations and normal karyotype represents a distinct genetic entity associated with a favorable clinical outcome.

J. Clin. Oncol. 28, 570-577 (2010)
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Purpose CEBPA mutations are found as either biallelic (biCEBPA) or monoallelic (moCEBPA). We set out to explore whether the kind of CEBPA mutation is of prognostic relevance in cytogenetically normal (CN) acute myeloid leukemia (AML). Patients and Methods: Four hundred sixty-seven homogeneously treated patients with CN-AML were subdivided into moCEBPA, biCEBPA, and wild-type (wt) CEBPA patients. The subgroups were analyzed for clinical parameters and for additional mutations in the NPM1, FLT3, and MLL genes. Furthermore, we obtained gene expression profiles using oligonucleotide microarrays. Results: Only patients with biCEBPA had an improved median overall survival when compared with patients with wtCEBPA (not reached v 20.4 months, respectively; P = .018), whereas patients with moCEBPA (20.9 months) and wtCEBPA had a similar outcome (P = .506). Multivariable analysis confirmed biCEBPA, but not moCEBPA, mutations as an independent favorable prognostic factor. Interestingly, biCEBPA mutations, compared with wtCEBPA, were never associated with mutated NPM1 (0% v 43%, respectively; P < .001) and rarely associated with FLT3 internal tandem duplication (ITD; 5% v 23%, respectively; P = .059), whereas patients with moCEBPA had a similar frequency of mutated NPM1 and a significantly higher association with FLT3-ITD compared with patients with wtCEBPA (44% v 23%, respectively; P = .037). Furthermore, patients with biCEBPA showed a homogeneous gene expression profile that was characterized by downregulation of HOX genes, whereas patients with moCEBPA showed greater heterogeneity in their gene expression profiles. Conclusion: Biallelic disruption of the N and C terminus of CEBPA is required for the favorable clinical outcome of CEBPA-mutated patients and represents a distinct molecular subtype of CN-AML with a different frequency of associated gene mutations. These findings are of great significance for risk-adapted therapeutic strategies in AML.
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Publication type Article: Journal article
Document type Scientific Article
Keywords MINIMAL RESIDUAL DISEASE; BINDING-PROTEIN-ALPHA; C/EBP-ALPHA; PROGNOSTIC-SIGNIFICANCE; EXPRESSION PROFILE; TANDEM DUPLICATION; RELAPSE SAMPLES; AML; FLT3; CYTOGENETICS
Language english
Publication Year 2010
HGF-reported in Year 2010
ISSN (print) / ISBN 0732-183X
e-ISSN 1527-7755
Journal Journal of Clinical Oncology - JCO
Quellenangaben Volume: 28, Issue: 4, Pages: 570-577 Article Number: , Supplement: ,
Publisher American Society of Clinical Oncology
Publishing Place Alexandria
Reviewing status Peer reviewed
Institute(s) CCG Pathogenesis of Acute Myeloid Leukemia (KKG-KPL)
POF-Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Research field(s) Immune Response and Infection
PSP Element(s) G-521000-001
PubMed ID 20038735
DOI 10.1200/JCO.2008.21.6010
Erfassungsdatum 2010-12-31
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