Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1
Abstract
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/EBP alpha), while lacking such mutations.
We found that in these leukemias, the CEBPA gene was silenced, which was associated with frequent promoter hyper-methylation. The leukemias phenotypically showed aberrant expression of Tcell 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 hemaopoitic 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.