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Cancer Res. 2010 Oct 1;70(19):7411-20. doi: 10.1158/0008-5472.CAN-10-1438. Epub 2010 Sep 28.

Activation-induced cytidine deaminase accelerates clonal evolution in BCR-ABL1-driven B-cell lineage acute lymphoblastic leukemia.

Author information

1
Childrens Hospital Los Angeles and Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, USA.

Abstract

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.

PMID:
20876806
PMCID:
PMC2948648
DOI:
10.1158/0008-5472.CAN-10-1438
[Indexed for MEDLINE]
Free PMC Article

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