Isotype-switched follicular lymphoma displays dissociation between activation-induced cytidine deaminase expression and somatic hypermutation

Abstract

In B-cells, activation-induced cytidine deaminase (AID) is required for somatic hypermutation (SHM) and class switch recombination (CSR) of immunoglobulin genes. AID introduces mutations in immunoglobulin variable regions (IGV) during B-cell receptor affinity maturation, but may also introduce aberrant mutations into non-immunoglobulin genes, most commonly BCL6. Follicular lymphoma (FL) B-cells constitutively express AID and undergo CSR, SHM and aberrant SHM. We have studied AID expression, the presence of SHM mutations, CSR, and aberrant SHM in BCL6 in a cohort of 75 FL patients. Whereas IgM-expressing (non-switched) FL were characterized by an expected positive correlation between AID and IGV and BCL6 mutations, isotype-switched FL showed dissociation between AID expression and aberrant SHM, and inverse correlation between SHM and AID expression. Our results unveil two manifest biological subgroups of FL and indicate that the specific dissociation between AID and SHM after isotype switch may correlate with the clinical outcome of this heterogeneous disease.

The problem of pulmonary embolism diagnosis in pregnancy

“…Paradoxically, FLLC fail to switch the functional IGH allele, suggesting dependence on IgM signalling at this stage. In contrast, many diagnosed FL cases have undergone CSR of their B-cell receptor (BCR) (Sachen et al, 2012;Scherer et al, 2015). Therefore, class-switched FL cells have apparently lost the characteristic dependency of FLLC on IgM signalling for recruitment into the GC.…”

“…Therefore, class-switched FL cells have apparently lost the characteristic dependency of FLLC on IgM signalling for recruitment into the GC. In addition, expression of activation-induced deaminase (AID) seems to be dissociated from somatic hypermutation (SHM) and aberrant SHM in class-switched FL (Scherer et al, 2015).…”

“…We explored whether class switching indicated a more aggressive FL subgroup with reduced dependence on the GC microenvironment by analysing clinical outcome parameters in a well-characterized prospective cohort of 69 FL cases (Scherer et al, 2015) (Table I). Patients not suffering from pruritus or B symptoms, without disease progression of more than 50% in the preceding 6 months, without life-endangering lymphoma infiltration, without compression of a vital organ by a tumour mass, without bulky disease (thoracic tumour mass >7Á5 cm; other locations >5 cm), and without relevant cytopenia due to lymphoma bone marrow infiltration (Hb <100 g/l, neutrophils <1Á5 9 10 9 /l or platelets <100 9 10 9 /l) were initially managed by watchful waiting.…”

“…To find a better biological surrogate than isotype for dependency on IgM-mediated GC signals, we reconstructed a 'primordial' unmutated IGH VDJ sequence from individual full-length IGH VDJ transcript sequences (Scherer et al, 2015) by an online tool (http://clip.med.yale.edu/sel/germline.php) using Somatic Diversification Algorithm (Volpe et al, 2006;Hershberg et al, 2008). In 65 cases with successful reconstruction of the primordial IGH VDJ sequence, selection pressure on diversifying IGH VDJ sequences was assessed with the 'Focused Test' (http://clip.med.yale.edu/sel/ index.php) (Hershberg et al, 2008).…”

CACTUS: integrating clonal architecture with genomic clustering and transcriptome profiling of single tumor cells

“…In addition, FL cells are continuously exposed to a physiological mutator mechanism, i.e. constitutive expression and action of activation induced cytidine deamidase (AID) (6). AID focuses on B-cell receptor (BCR) loci and results in highly mutated BCR heavy and light chain encoding genes (7).…”