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

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.