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

Publication ,  Journal Article
Wouters, BJ; Jordà, MA; Keeshan, K; Louwers, I; Erpelinck-Verschueren, CAJ; Tielemans, D; Langerak, AW; He, Y; Yashiro-Ohtani, Y; Zhang, P ...
Published in: Blood
November 15, 2007

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.

Duke Scholars

Published In

Blood

DOI

ISSN

0006-4971

Publication Date

November 15, 2007

Volume

110

Issue

10

Start / End Page

3706 / 3714

Location

United States

Related Subject Headings

  • Receptor, Notch1
  • Oligonucleotide Array Sequence Analysis
  • Mutation
  • Mice, Transgenic
  • Mice
  • Leukemia-Lymphoma, Adult T-Cell
  • Leukemia, Myeloid, Acute
  • Immunology
  • Humans
  • Gene Silencing
 

Citation

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MLA
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Wouters, B. J., Jordà, M. A., Keeshan, K., Louwers, I., Erpelinck-Verschueren, C. A. J., Tielemans, D., … Delwel, R. (2007). Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1. Blood, 110(10), 3706–3714. https://doi.org/10.1182/blood-2007-02-073486
Wouters, Bas J., Meritxell Alberich Jordà, Karen Keeshan, Irene Louwers, Claudia A. J. Erpelinck-Verschueren, Dennis Tielemans, Anton W. Langerak, et al. “Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1.Blood 110, no. 10 (November 15, 2007): 3706–14. https://doi.org/10.1182/blood-2007-02-073486.
Wouters BJ, Jordà MA, Keeshan K, Louwers I, Erpelinck-Verschueren CAJ, Tielemans D, et al. Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1. Blood. 2007 Nov 15;110(10):3706–14.
Wouters, Bas J., et al. “Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1.Blood, vol. 110, no. 10, Nov. 2007, pp. 3706–14. Pubmed, doi:10.1182/blood-2007-02-073486.
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. Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1. Blood. 2007 Nov 15;110(10):3706–3714.

Published In

Blood

DOI

ISSN

0006-4971

Publication Date

November 15, 2007

Volume

110

Issue

10

Start / End Page

3706 / 3714

Location

United States

Related Subject Headings

  • Receptor, Notch1
  • Oligonucleotide Array Sequence Analysis
  • Mutation
  • Mice, Transgenic
  • Mice
  • Leukemia-Lymphoma, Adult T-Cell
  • Leukemia, Myeloid, Acute
  • Immunology
  • Humans
  • Gene Silencing