Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1.
Gene expression profiling of acute myeloid leukemia (AML) allows the discovery of previously unrecognized molecular entities. Here, we identified a specific subgroup of AML, defined by an expression profile resembling that of AMLs with mutations in the myeloid transcription factor CCAAT/enhancer-binding protein alpha (C/EBPalpha), while lacking such mutations. We found that in these leukemias, the CEBPA gene was silenced, which was associated with frequent promoter hypermethylation. The leukemias phenotypically showed aberrant expression of T-cell genes, of which CD7 was most consistent. We identified 2 mechanisms that may contribute to this phenotype. First, absence of Cebpa led to up-regulation of specific T-cell transcripts (ie, Cd7 and Lck) in hematopoietic stem cells isolated from conditional Cebpa knockout mice. Second, the enhanced expression of TRIB2, which we identify here as a direct target of the T-cell commitment factor NOTCH1, suggested aberrantly activated Notch signaling. Putatively activating NOTCH1 mutations were found in several specimens of the newly identified subgroup, while a large set of control AMLs was mutation negative. A gene expression prediction signature allowed the detection of similar cases of leukemia in independent series of AML.
Wouters
Bas J
BJ
Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Jordà
Meritxell Alberich
MA
Keeshan
Karen
K
Louwers
Irene
I
Erpelinck-Verschueren
Claudia A J
CA
Tielemans
Dennis
D
Langerak
Anton W
AW
He
Yiping
Y
Yashiro-Ohtani
Yumi
Y
Zhang
Pu
P
Hetherington
Christopher J
CJ
Verhaak
Roel G W
RG
Valk
Peter J M
PJ
Löwenberg
Bob
B
Tenen
Daniel G
DG
Pear
Warren S
WS
Delwel
Ruud
R
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics*; D002478:Cells, Cultured; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D020868:Gene Silencing; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D051881:Receptor, Notch1 / Q000235:genetics*
D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1