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

Journal Article (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

  • PMC2077318

International Standard Serial Number (ISSN)

  • 0006-4971

Digital Object Identifier (DOI)

  • 10.1182/blood-2007-02-073486


  • eng

Conference Location

  • United States