The Journal of Experimental Medicine
StemCell Technologies
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Published online May 7, 2007
doi:10.1084/jem.20062662
The Journal of Experimental Medicine, Vol. 204, No. 5, 1157-1166
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Feldhahn et al.
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ARTICLE

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

Niklas Feldhahn1,2, Nadine Henke1,3, Kai Melchior1,2, Cihangir Duy1,2, Bonaventure Ndikung Soh1,3, Florian Klein1,3, Gregor von Levetzow3, Bernd Giebel3, Aihong Li4, Wolf-Karsten Hofmann5, Hassan Jumaa6, and Markus Müschen1,2

1 Leukemia Research Program, Childrens Hospital Los Angeles, 2 Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90027
3 Biologisch Medizinisches Forschungszentrum, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
4 Department of Medical Biosciences, Pathology, Umea University, SE-901 87 Umea, Sweden
5 Department of Hematology and Oncology, University Hospital Benjamin Franklin, 12200 Berlin, Germany
6 Max-Planck Institute for Immunobiology, D-79108 Freiburg, Germany

CORRESPONDENCE Markus Müschen: mmuschen{at}chla.usc.edu

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.

Abbreviations used: Abelson-MuLV, Abelson murine leukemia virus; AID, activation-induced cytidine deaminase; ALL, acute lymphoblastic leukemia; CSR, class-switch recombination; DNA-SSB, DNA single-strand breaks; LBC, lymphoid blast crisis; LM-PCR, ligation-mediated PCR; Ph, Philadelphia chromosome; SHM, somatic hypermutation; siRNA, small interfering RNA; V, variable.


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