PuSH - Publikationsserver des Helmholtz Zentrums München

Greif, P.A. ; Konstandin, N.P. ; Metzeler, K.H.* ; Herold, T.* ; Pasalic, Z.* ; Ksienzyk, B.* ; Dufour, A.* ; Schneider, F.* ; Schneider, S.* ; Kakadia, P.M. ; Braess, J.* ; Sauerland, M.C.* ; Berdel, W.E.* ; Büchner, T.* ; Woermann, B.J.* ; Hiddemann, W. ; Spiekermann, K. ; Bohlander, S.K.

RUNX1 mutations in cytogenetically normal acute myeloid leukemia are associated with poor prognosis and up-regulation of lymphoid genes.

Haematologica 97, 1909-1915 (2012)
Verlagsversion Volltext DOI PMC
Open Access Gold
Background. The RUNX1 (AML1) gene is a frequent mutational target in myelodysplastic syndromes and acute myeloid leukemia. Previous studies suggested that RUNX1 mutations may have pathological and prognostic implications.Design and Methods. We have screened 93 cytogenetically normal acute myeloid leukemia patients for RUNX1 mutations by capillary sequencing of genomic DNA. Mutation status was then correlated with clinical data and gene expression profiles.Results. We identified 15 out of 93 cytogenetically normal acute myeloid leukemia patients with RUNX1 mutations (16.1 %). 73 CN-AML patients were enrolled in the AMLCG-99 trial and carried 10 RUNX1 mutations (13.7%). Among these 73 patients RUNX1 mutations were significantly associated with older age, male sex, absence of NPM1 mutations and presence of MLL-partial tandem duplications. Moreover, RUNX1 mutated patients had a lower complete remission rate (30% vs. 73% p=0.01) and shorter relapse-free survival (RFS; p=0.002; 3-year RFS 0% vs. 30.4%) and overall survival (OS; p<0.001; 3-year OS 0% vs. 34.4%) than RUNX1 wild type patients. RUNX1 mutations remained associated with shorter OS in a multivariate model including the covariates age and the European Leukemia Net (ELN) acute myeloid leukemia genetic classification. Patients with RUNX1 mutations showed a unique gene expression pattern with differential expression of 85 genes. The most prominently upregulated genes in RUNX1 mutated CN-AML include lymphoid regulators like HOPX (HOP homeobox), DNTT (deoxynucleotidyltransferase, terminal) and BLNK (B cell linker) indicating lineage infidelity. Conclusions. Our findings firmly establish RUNX1 mutations as marker of poor prognosis and provide insights into the pathogenesis of RUNX1 mutation positive AML.
Altmetric
Weitere Metriken?
[➜Einloggen]
Zusatzinfos bearbeiten [➜Einloggen]
Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Runx1 ; Mutations ; Prognosis ; Acute Myeloid Leukemia; Point Mutations ; Group-b ; Expression ; Cancer ; Older
ISSN (print) / ISBN 0390-6078
e-ISSN 1592-8721
Zeitschrift Haematologica - The Hematology Journal
Quellenangaben Band: 97, Heft: 12, Seiten: 1909-1915 Artikelnummer: , Supplement: ,
Verlag Ferrata Storti Foundation
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) CCG Pathogenesis of Acute Myeloid Leukemia (KKG-KPL)