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  Activation-induced cytidine deaminase acts as a mutator in BCR-ABL1-transformed acute lymphoblastic leukemia cells

Feldhahn, N., Henke, N., Melchoir, K., Duy, C., Ndikung Soh, B., Klein, F., et al. (2007). Activation-induced cytidine deaminase acts as a mutator in BCR-ABL1-transformed acute lymphoblastic leukemia cells. The Journal of Experimental Medicine, 204, 1157-1166.

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 Creators:
Feldhahn, Niklas, Author
Henke, Nadine, Author
Melchoir, Kai, Author
Duy, Cihangir, Author
Ndikung Soh, Bonaventure, Author
Klein, Florian, Author
von Levetzow, Gregor, Author
Giebel, Bernd, Author
Li, Aihong, Author
Hofmann, Wolf-Karsten, Author
Jumaa, Hassan1, Author              
Müschen, Markus, Author
Affiliations:
1Research Group and Chair of Molecular Immunology of the University of Freiburg, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, ou_2243645              

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 Abstract: The Philadelphia chromosome (Ph) encoding the oncogenic BCR-ABL1 kinase defines a subset of acute lymphoblastic leukemia (ALL) with a particularly unfavorable prognosis. ALL cells are derived from B cell precursors in most cases and typically carry rearranged immunoglobulin heavy chain (IGH) variable (V) region genes devoid of somatic mutations. Somatic hypermutation is restricted to mature germinal center B cells and depends on activation-induced cytidine deaminase (AID). Studying AID expression in 108 cases of ALL, we detected AID mRNA in 24 of 28 Ph+ ALLs as compared with 6 of 80 Ph- ALLs. Forced expression of BCR-ABL1 in Ph- ALL cells and inhibition of the BCR-ABL1 kinase showed that aberrant expression of AID depends on BCR-ABL1 kinase activity. Consistent with aberrant AID expression in Ph+ ALL, IGH V region genes and BCL6 were mutated in many Ph+ but unmutated in most Ph- cases. In addition, AID introduced DNA single-strand breaks within the tumor suppressor gene CDKN2B in Ph+ ALL cells, which was sensitive to BCR-ABL1 kinase inhibition and silencing of AID expression by RNA interference. These findings identify AID as a BCR-ABL1-induced mutator in Ph+ ALL cells, which may be relevant with respect to the particularly unfavorable prognosis of this leukemia subset.

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Language(s): eng - English
 Dates: 2007
 Publication Status: Published in print
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 Rev. Type: Peer
 Identifiers: eDoc: 329268
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Title: The Journal of Experimental Medicine
  Alternative Title : JEM
Source Genre: Journal
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Pages: - Volume / Issue: 204 Sequence Number: - Start / End Page: 1157 - 1166 Identifier: -