Activation-induced cytidine deaminase acts as a mutator in BCR-ABL1-transformed acute lymphoblastic leukemia cells
2007 (English)In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 204, no 5, 1157-1166 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2007. Vol. 204, no 5, 1157-1166 p.
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:umu:diva-22957DOI: 10.1084/jem.20062662ISI: 000246467600019PubMedID: 17485517OAI: oai:DiVA.org:umu-22957DiVA: diva2:218744