ATM Increases Activation-Induced Cytidine Deaminase Activity at Downstream S Regions during Class-Switch Recombination

Abstract In B cells, somatic hypermutation (SHM) and class switch recombination (CSR) depend on the activation-induced cytidine deaminase (AID) gene product, although the precise mode of action of AID remains unknown. Because some chronic lymphocytic leukemia (CLL) B cells can undergo CSR without SHM, it constitutes a useful model to dissect AID function. In this work, we have studied AID expression, the presence of mutations in the preswitch μ DNA region, CSR, and the SHM in 65 CLL patients. Our results demonstrate that unmutated CLL B cells can constitutively express AID and that AID expression is associated with the presence of mutations in the preswitch region and in clonally related isotype-switched transcripts. They also demonstrate that in CLL without constitutive AID expression, AID induction on stimulation results in preswitch mutations and the CSR process. Our results show a dissociation between SHM and CSR in CLL and suggest that, in this disease, AID would require additional help for carrying out the SHM process.

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The Block in Immunoglobulin Class Switch Recombination Caused by Activation-Induced Cytidine Deaminase Deficiency Occurs Prior to the Generation of DNA Double Strand Breaks in Switch μ Region

The Journal of Immunology ◽

10.4049/jimmunol.171.5.2504 ◽

2003 ◽

Vol 171 (5) ◽

pp. 2504-2509 ◽

Cited By ~ 76

Author(s):

Nadia Catalan ◽

Françoise Selz ◽

Kohsuke Imai ◽

Patrick Revy ◽

Alain Fischer ◽

...

Keyword(s):

Cytidine Deaminase ◽

Class Switch Recombination ◽

Double Strand Breaks ◽

Dna Double Strand Breaks ◽

Strand Breaks ◽

Immunoglobulin Class ◽

Class Switch ◽

Activation Induced Cytidine Deaminase

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High expression of AID and active class switch recombination might account for a more aggressive disease in unmutated CLL patients: link with an activated microenvironment in CLL disease

Blood ◽

10.1182/blood-2009-12-257758 ◽

2010 ◽

Vol 115 (22) ◽

pp. 4488-4496 ◽

Cited By ~ 56

Author(s):

Florencia Palacios ◽

Pilar Moreno ◽

Pablo Morande ◽

Cecilia Abreu ◽

Agustín Correa ◽

...

Keyword(s):

B Cells ◽

Cytidine Deaminase ◽

Class Switch Recombination ◽

Lymphocytic Leukemia ◽

Small Subset ◽

Ki 67 ◽

Tissue Microenvironment ◽

Class Switch ◽

Activation Induced Cytidine Deaminase ◽

Progression Markers

Abstract Interaction of chronic lymphocytic leukemia (CLL) B cells with tissue microenvironment has been suggested to favor disease progression by promoting malignant B-cell growth. Previous work has shown expression in peripheral blood (PB) of CLL B cells of activation-induced cytidine deaminase (AID) among CLL patients with an unmutated (UM) profile of immunoglobulin genes and with ongoing class switch recombination (CSR) process. Because AID expression results from interaction with activated tissue microenvironment, we speculated whether the small subset with ongoing CSR is responsible for high levels of AID expression and could be derived from this particular microenvironment. In this work, we quantified AID expression and ongoing CSR in PB of 50 CLL patients and characterized the expression of different molecules related to microenvironment interaction. Our results show that among UM patients (1) high AID expression is restricted to the subpopulation of tumoral cells ongoing CSR; (2) this small subset expresses high levels of proliferation, antiapoptotic and progression markers (Ki-67, c-myc, Bcl-2, CD49d, and CCL3/4 chemokines). Overall, this work outlines the importance of a cellular subset in PB of UM CLL patients with a poor clinical outcome, high AID levels, and ongoing CSR, whose presence might be a hallmark of a recent contact with the microenvironment.

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