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Herold, T. ; Metzeler, K.H. ; Vosberg, S. ; Hartmann, L. ; Röllig, C.* ; Stölzel, F.* ; Schneider, S.* ; Hubmann, M. ; Zellmeier, E.* ; Ksienzyk, B.* ; Jurinovic, V.* ; Pasalic, Z.* ; Kakadia, P.M.* ; Dufour, A.* ; Graf, A.* ; Krebs, S.* ; Blum, H.* ; Sauerland, M.C.* ; Büchner, T.* ; Berdel, W.E.* ; Woermann, B.J.* ; Bornhäuser, M.* ; Ehninger, G.* ; Mansmann, U.* ; Hiddemann, W. ; Bohlander, S.K.* ; Spiekermann, K. ; Greif, P.A.

Isolated trisomy 13 defines a genetically homogenous AML subgroup with high frequency of mutations in spliceosome genes and poor prognosis.

Blood 124, 1304-1311 (2014)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
Isolated trisomy 13 (AML+13) is a rare chromosomal abnormality in acute myeloid leukemia (AML), and its prognostic relevance is poorly characterized. We analyzed the clinical course of 34 AML+13 patients enrolled in the German AMLCG-1999 and SAL trials and studied their biological characteristics by exome sequencing, targeted sequencing of candidate genes and gene expression profiling. Relapse-free (RFS) and overall survival (OS) of AML+13 patients were inferior compared to other ELN Intermediate-II patients (n=855) (median RFS, 7.8 vs 14.1 months, p=0.006; median OS 9.3 vs. 14.8 months, p=0.004). Besides the known high frequency of RUNX1 mutations (75%), we identified mutations in spliceosome components in 88%, including SRSF2 codon 95 mutations in 81%, of AML+13 patients. Moreover, recurring mutations were detected in ASXL1 (44%) and BCOR (25%). Two patients carried mutations in CEBPZ, suggesting that CEBPZ is a novel recurrently mutated gene in AML. Gene expression analysis revealed a homogenous expression profile including upregulation of FOXO1 and FLT3 and downregulation of SPRY2. This is the most comprehensive clinical and biological characterization of AML+13 to date, and reveals a striking clustering of lesions in a few genes, defining AML+13 as a genetically homogenous leukemia subgroup with alterations in a few critical cellular pathways. These studies were registered at clinicaltrials.gov, identifiers: AMLCG-1999: NCT00266136; AML96: NCT00180115; AML2003: NCT00180102; and AML60+: NCT00893373.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Acute Myeloid-leukemia; Chronic Lymphocytic-leukemia; Increased Flt3 Expression; European Leukemianet; Down-regulation; Cancer; Recommendations; Consolidation; Mitoxantrone; Abnormality
ISSN (print) / ISBN 0006-4971
e-ISSN 1528-0020
Journal Blood
Quellenangaben Volume: 124, Issue: 8, Pages: 1304-1311 Article Number: , Supplement: ,
Publisher American Society of Hematology
Publishing Place Washington
Reviewing status Peer reviewed
Institute(s) CCG Pathogenesis of Acute Myeloid Leukemia (KKG-KPL)