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Blood, 15 November 2007, Vol. 110, No. 10, pp. 3706-3714. Prepublished online as a Blood First Edition Paper on August 1, 2007; DOI 10.1182/blood-2007-02-073486.
NEOPLASIA Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH11 Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands; 2 Harvard Institutes of Medicine, Boston, MA; 3 Abramson Family Cancer Research Institute and Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia; and 4 Department of Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands
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
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| Copyright © 2007 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||||
), 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. 
