Activation-induced cytidine deaminase splicing patterns in chronic lymphocytic leukemia

IGHV-unmutated and IGHV-mutated chronic lymphocytic leukemia cells produce activation-induced deaminase protein with a full range of biologic functions

“…Previous studies have associated AID expression with the presence of adverse prognostic markers 18,20,21,[24][25][26] and one study retrospectively associated PB AID mRNA expression with progression-free survival, not OS, possibly because of the median follow-up of only 48 months. 26 Therefore, ours is the first prospective analysis with a long median follow-up (144 months) and a sufficient number of events to demonstrate that AID predicts OS very powerfully, with a 10-year difference in survival between patients with AID ϩ and AID Ϫ disease ( Figure 6G). A complementary study examining AID protein in tissues suggested such an association, albeit in a much smaller cohort.…”

“…Alternatively, AID activity in U-CLL may be actively inhibited from targeting or acting on IGV genes because in vivo the accessibility of the V regions to AID has been blocked (eg, by changes in chromatin structure) or is not achieved because of the lack of production of a targeting molecule by U-CLL clones. Finally, AID activity could be inhibited by the AID splice variants produced 26,48 or the tissue microenvironments of U-CLL patients.…”

“…[14][15][16][17][18] AID activity focused elsewhere ("aberrant" or "off-target" SHM 3,19 ) can lead to mutations, deletions, or translocations outside of the IG locus, as in GC-derived lymphomas. [3][4][5] However, such a role for AID in CLL has been questioned for several reasons: (1) although circulating CLL cells can express AID mRNA, [20][21][22] the number of such cells is exceedingly low (0.01%-0.2%) 22 ; (2) AID protein synthesis by these same cells has not been demonstrated 18,[20][21][22][23] ; (3) demonstration of the full range of AID functions is lacking in CLL, for example, by failure of cells to demonstrate SHM, especially for U-CLL clones, even on stimulation and induction of AID mRNA, 21 thereby creating the apparent paradox that U-CLL patients express more AID mRNA than M-CLL patients yet exhibit no or minimal SHM; and (4) despite association with several prognostic markers, 20,21,[24][25][26] no prospective analysis linking AID expression and disease severity has been performed.…”

Molecular Evidence for Antigen Drive in the Natural History of Mantle Cell Lymphoma

“…25 More specifically, to produce plasmid DNA calibrators that contained the target gene sequences for each AID variant, we first amplified each transcript in three separate qualitative RQ-PCR reactions ( Table 1). Each PCR product (single band) was gel purified (QIAquick Gel Extraction Kit; QIAGEN, Hilden, Germany), cloned into the pCR2.1 vector (TA Cloning Kit; Invitrogen, Paisley, UK), and sequenced (Beckman Coulter CEQ 8000 sequencer; Beckman Coulter, Fullerton, CA) to confirm the insert.…”

Immunoglobulin class switch recombination in chronic lymphocytic leukemia

“…In HSM, AID directly increases the number of mutations within the variable region, while in CSR, AID deaminates nucleosides as an initiating step in intrachromosomal recombination. Interestingly, differential patterns of AID splicing have been observed in (1) IGVH unmutated as compared to mutated CLL and (2) mutated IgGþ CLL as compared to mutated IgMþIgDþ CLL, suggesting that AID isoforms may be determinants of both HSM and CSR [12]. Palacios et al hypothesized that microenvironmental activation of AID could explain the CSR observed among a subset of CLL cells in otherwise unswitched IgMþ CLL [13].…”