Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1.


Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Wouters, BJ; Jordà, MA; Keeshan, K; Louwers, I; Erpelinck-Verschueren, CAJ; Tielemans, D; Langerak, AW; He, Y; Yashiro-Ohtani, Y; Zhang, P; Hetherington, CJ; Verhaak, RGW; Valk, PJM; Löwenberg, B; Tenen, DG; Pear, WS; Delwel, R

Published Date

  • November 15, 2007

Published In

Volume / Issue

  • 110 / 10

Start / End Page

  • 3706 - 3714

PubMed ID

  • 17671232

Pubmed Central ID

  • 17671232

International Standard Serial Number (ISSN)

  • 0006-4971

Digital Object Identifier (DOI)

  • 10.1182/blood-2007-02-073486


  • eng

Conference Location

  • United States