| First Author | Gruber TA | Year | 2010 |
| Journal | Cancer Res | Volume | 70 |
| Issue | 19 | Pages | 7411-20 |
| PubMed ID | 20876806 | Mgi Jnum | J:164646 |
| Mgi Id | MGI:4834925 | Doi | 10.1158/0008-5472.CAN-10-1438 |
| Citation | Gruber TA, et al. (2010) Activation-induced cytidine deaminase accelerates clonal evolution in BCR-ABL1-driven B-cell lineage acute lymphoblastic leukemia. Cancer Res 70(19):7411-20 |
| abstractText | 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. |
