Activation-induced cytidine deaminase acts as a mutator in BCR-ABL1-transformed acute lymphoblastic leukemia cells.
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.
Feldhahn
Niklas
N
Leukemia Research Program, Childrens Hospital Los Angeles, University of Southern California, Los Angeles, CA 90027, USA.
Henke
Nadine
N
Melchior
Kai
K
Duy
Cihangir
C
Soh
Bonaventure Ndikung
BN
Klein
Florian
F
von Levetzow
Gregor
G
Giebel
Bernd
B
Li
Aihong
A
Hofmann
Wolf-Karsten
WK
Jumaa
Hassan
H
Müschen
Markus
M
D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D001483:Base Sequence; D015153:Blotting, Western; D003564:Cytidine Deaminase / Q000378:metabolism*; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D016259:Genes, myc / Q000235:genetics; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D009841:Oligonucleotides; D010677:Philadelphia Chromosome; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016415:Sequence Alignment; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
C084103:BCL6 protein, human; D004268:DNA-Binding Proteins; D007135:Immunoglobulin Variable Region; D009841:Oligonucleotides; D051560:Proto-Oncogene Proteins c-bcl-6; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase