Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype.
Among acute myeloid leukemia (AML) patients with a normal karyotype (CN-AML), NPM1 and CEBPA mutations define World Health Organization 2008 provisional entities accounting for approximately 60% of patients, but the remaining 40% are molecularly poorly characterized. Using whole-exome sequencing of one CN-AML patient lacking mutations in NPM1, CEBPA, FLT3-ITD, IDH1, and MLL-PTD, we newly identified a clonal somatic mutation in BCOR (BCL6 corepressor), a gene located on chromosome Xp11.4. Further analyses of 553 AML patients showed that BCOR mutations occurred in 3.8% of unselected CN-AML patients and represented a substantial fraction (17.1%) of CN-AML patients showing the same genotype as the AML index patient subjected to whole-exome sequencing. BCOR somatic mutations were: (1) disruptive events similar to the germline BCOR mutations causing the oculo-facio-cardio-dental genetic syndrome; (2) associated with decreased BCOR mRNA levels, absence of full-length BCOR, and absent or low expression of a truncated BCOR protein; (3) virtually mutually exclusive with NPM1 mutations; and (4) frequently associated with DNMT3A mutations, suggesting cooperativity among these genetic alterations. Finally, BCOR mutations tended to be associated with an inferior outcome in a cohort of 422 CN-AML patients (25.6% vs 56.7% overall survival at 2 years; P = .032). Our results for the first time implicate BCOR in CN-AML pathogenesis.
MLL Munich Leukemia Laboratory, Munich, Germany.
Vera
V
Grossmann
Enrico
E
Tiacci
Antony B
AB
Holmes
Alexander
A
Kohlmann
Maria Paola
MP
Martelli
Wolfgang
W
Kern
Ariele
A
Spanhol-Rosseto
Hans-Ulrich
HU
Klein
Martin
M
Dugas
Sonja
S
Schindela
Vladimir
V
Trifonov
Susanne
S
Schnittger
Claudia
C
Haferlach
Renato
R
Bassan
Victoria A
VA
Wells
Orietta
O
Spinelli
Joseph
J
Chan
Roberta
R
Rossi
Stefano
S
Baldoni
Luca
L
De Carolis
Katharina
K
Goetze
Hubert
H
Serve
Rudolf
R
Peceny
Karl-Anton
KA
Kreuzer
Daniel
D
Oruzio
Giorgina
G
Specchia
Francesco
F
Di Raimondo
Francesco
F
Fabbiano
Marco
M
Sborgia
Arcangelo
A
Liso
Laurent
L
Farinelli
Alessandro
A
Rambaldi
Laura
L
Pasqualucci
Raul
R
Rabadan
Torsten
T
Haferlach
Brunangelo
B
Falini
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015331:Cohort Studies; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D000090205:DNA Methyltransferase 3A; D059472:Exome / Q000235:genetics*; D017809:Fatal Outcome; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics*; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics; D000090243:Nucleophosmin; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D016019:Survival Analysis; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
C411984:BCOR protein, human; D050676:Core Binding Factor Alpha 2 Subunit; C000717967:DNMT3A protein, human; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C493728:RUNX1 protein, human; D012097:Repressor Proteins; D000090243:Nucleophosmin; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3