Activation-induced cytidine deaminase accelerates clonal evolution in BCR-ABL1-driven B-cell lineage acute lymphoblastic leukemia.
Activation-induced cytidine deaminase (AID) is required for somatic hypermutation and immunoglobulin (Ig) class switch recombination in germinal center (GC) B cells. Occasionally, AID can target non-Ig genes and thereby promote GC B-cell lymphomagenesis. We recently showed that the oncogenic BCR-ABL1 kinase induces aberrant expression of AID in pre-B acute lymphoblastic leukemia (ALL) and lymphoid chronic myelogenous leukemia blast crisis. To elucidate the biological significance of aberrant AID expression, we studied loss of AID function in a murine model of BCR-ABL1 ALL. Mice transplanted with BCR-ABL1-transduced AID(-/-) bone marrow had prolonged survival compared with mice transplanted with leukemia cells generated from AID(+/+) bone marrow. Consistent with a causative role of AID in genetic instability, AID(-/-) leukemia had a lower frequency of amplifications and deletions and a lower frequency of mutations in non-Ig genes, including Pax5 and Rhoh compared with AID(+/+) leukemias. AID(-/-) and AID(+/+) ALL cells showed a markedly distinct gene expression pattern, and AID(-/-) ALL cells failed to downregulate a number of tumor-suppressor genes including Rhoh, Cdkn1a (p21), and Blnk (SLP65). We conclude that AID accelerates clonal evolution in BCR-ABL1 ALL by enhancing genetic instability and aberrant somatic hypermutation, and by negative regulation of tumor-suppressor genes.
Gruber
Tanja Andrea
TA
Childrens Hospital Los Angeles and Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, USA.
Chang
Mi Sook
MS
Sposto
Richard
R
Müschen
Markus
M
D000818:Animals; D002999:Clone Cells; D003564:Cytidine Deaminase / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D016044:Fusion Proteins, bcr-abl; D005784:Gene Amplification; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D016147:Genes, Tumor Suppressor; D016313:Genes, abl; D016158:Genes, p53; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D019061:src-Family Kinases / Q000378:metabolism; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D016044:Fusion Proteins, bcr-abl; D019061:src-Family Kinases; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase