GATA2 zinc finger 1 mutations associated with biallelic CEBPA mutations define a unique genetic entity of acute myeloid leukemia.
Cytogenetically normal acute myeloid leukemia (CN-AML) with biallelic CEBPA gene mutations (biCEPBA) represents a distinct disease entity with a favorable clinical outcome. So far, it is not known whether other genetic alterations cooperate with biCEBPA mutations during leukemogenesis. To identify additional mutations, we performed whole exome sequencing of 5 biCEBPA patients and detected somatic GATA2 zinc finger 1 (ZF1) mutations in 2 of 5 cases. Both GATA2 and CEBPA are transcription factors crucial for hematopoietic development. Inherited or acquired mutations in both genes have been associated with leukemogenesis. Further mutational screening detected novel GATA2 ZF1 mutations in 13 of 33 biCEBPA-positive CN-AML patients (13/33, 39.4%). No GATA2 mutations were found in 38 CN-AML patients with a monoallelic CEBPA mutation and in 89 CN-AML patients with wild-type CEBPA status. The presence of additional GATA2 mutations (n=10) did not significantly influence the clinical outcome of 26 biCEBPA-positive patients. In reporter gene assays, all tested GATA2 ZF1 mutants showed reduced capacity to enhance CEBPA-mediated activation of transcription, suggesting that the GATA2 ZF1 mutations may collaborate with biCEPBA mutations to deregulate target genes during malignant transformation. We thus provide evidence for a genetically distinct subgroup of CN-AML. The German AML cooperative group trials 1999 and 2008 are registered with the identifiers NCT00266136 and NCT01382147 at www.clinicaltrials.gov.
Department of Internal Medicine 3, Ludwig-Maximilians-Universität (LMU) Munich, Marchioninistrasse 25, Munich, Germany.
Philipp A
PA
Greif
Annika
A
Dufour
Nikola P
NP
Konstandin
Bianka
B
Ksienzyk
Evelyn
E
Zellmeier
Belay
B
Tizazu
Jutta
J
Sturm
Tobias
T
Benthaus
Tobias
T
Herold
Marjan
M
Yaghmaie
Petra
P
Dörge
Karl-Peter
KP
Hopfner
Andreas
A
Hauser
Alexander
A
Graf
Stefan
S
Krebs
Helmut
H
Blum
Purvi M
PM
Kakadia
Stephanie
S
Schneider
Eva
E
Hoster
Friederike
F
Schneider
Martin
M
Stanulla
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
D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D020732:Cytogenetic Analysis; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D059472:Exome; D050989:GATA2 Transcription Factor / Q000737:chemistry / Q000235:genetics*; D005787:Gene Frequency; D006801:Humans; D059785:Karyotype; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011379:Prognosis; D015533:Transcriptional Activation; D016335:Zinc Fingers / Q000235:genetics
D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; D004273:DNA, Neoplasm; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human