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


METHODS
We screened 93 patients with cytogenetically normal acute myeloid leukemia for RUNX1 mutations by capillary sequencing of genomic DNA. Mutation status was then correlated with clinical data and gene expression profiles.


RESULTS
We found that 15 out of 93 (16.1%) patients with cytogenetically normal acute myeloid leukemia had RUNX1 mutations. Seventy-three patients were enrolled in the AMLCG-99 trial and carried ten 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% versus 73% P=0.01), lower relapse-free survival rate (3-year relapse-free survival 0% versus 30.4%; P=0.002) and lower overall survival rate (3-year overall survival 0% versus 34.4%; P<0.001) than patients with wild-type RUNX1. RUNX1 mutations remained associated with shorter overall survival in a multivariate model including age and the European Leukemia Net acute myeloid leukemia genetic classification as covariates. Patients with RUNX1 mutations showed a unique gene expression pattern with differential expression of 85 genes. The most prominently up-regulated genes in patients with RUNX1-mutated cytogenetically normal acute myeloid leukemia include lymphoid regulators such as HOP homeobox (HOPX), deoxynucleotidyltransferase (DNTT, terminal) and B-cell linker (BLNK), indicating lineage infidelity.


CONCLUSIONS
Our findings firmly establish that RUNX1 mutations are a marker of poor prognosis and provide insights into the pathogenesis of RUNX1 mutation-positive acute myeloid leukemia.
Department of Internal Medicine 3, Ludwig-Maximilians-Universität (LMU) Munich, Munich, Germany.
Philipp A
PA
Greif
Nikola P
NP
Konstandin
Klaus H
KH
Metzeler
Tobias
T
Herold
Zlatana
Z
Pasalic
Bianka
B
Ksienzyk
Annika
A
Dufour
Friederike
F
Schneider
Stephanie
S
Schneider
Purvi M
PM
Kakadia
Jan
J
Braess
Maria Cristina
MC
Sauerland
Wolfgang E
WE
Berdel
Thomas
T
Büchner
Bernhard J
BJ
Woermann
Wolfgang
W
Hiddemann
Karsten
K
Spiekermann
Stefan K
SK
Bohlander
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D015331:Cohort Studies; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015470:Leukemia, Myeloid, Acute / Q000145:classification / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D000090243:Nucleophosmin; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D012074:Remission Induction; D015996:Survival Rate
D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; D014408:Biomarkers, Tumor; D050676:Core Binding Factor Alpha 2 Subunit; C000716967:NPM1 protein, human; C493728:RUNX1 protein, human; D000090243:Nucleophosmin