Do CLL B cells correspond to naive or memory B-lymphocytes? Evidence for an active Ig switch unrelated to phenotype expression and Ig mutational pattern in B-CLL cells

Oppezzo, Pablo; Magnac, Christian; Bianchi, Sergio; Vuillier, Françoise; Tiscornia, Adriana; Dumas, Gérard; Payelle-Brogard, Béatrice; Ajchenbaum‐Cymbalista, Florence; Dighiero, Guillaume; Pritsch, Otto

doi:10.1038/sj.leu.2402731

Cited by 38 publications

(33 citation statements)

References 46 publications

(47 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…UM cases showed a longer CDR3 region (from 13 to 28 amino acids; median = 21) than M cases (from 12 to 20 646 Pimentel et al amino acids; median = 15). This difference was statistically significant (p < 0.001, by both Student's t-test and the Wilcoxon test), in agreement with previous data in the literature (Opezzo et al, 2002;Duke et al, 2003). Here again, we do not know if these findings reflect genetic and/or environmental factors or result from the small number of patients analysed by us.…”

supporting

confidence: 82%

Use of V H, D and J H immunoglobulin gene segments in Brazilian patients with chronic lymphocytic leukaemia (CLL)

et al. 2008

View full text Add to dashboard Cite

Chronic lymphocytic leukaemia (CLL) is a haematological malignancy for which reliable prognostic markers are needed in view of its clinical heterogeneity. In approximately 50% of CLL patients, immunoglobulin (Ig) rearrangements are modified by somatic hypermutation (SHM), a process that represents a reliable prognostic indicator of favourable progression. In this study, we investigated SHM in 37 Brazilian CLL patients and identified the preferential involvement of specific immunoglobulin gene families and segments through PCR-amplified fragments or subcloned fragments. Forty-one rearrangements were observed and 37 of them were functional. A 98% homology cut-off with germinal sequences showed 18 patients (48.7%) with SHM. Unmutated cases showed a poorer clinical outcome. V H 3 was the most frequent V H family, followed by V H 4. The V H 4-39 segment was the most frequently used, mainly in unmutated cases, while the V H 3 family was predominant in mutated cases. The D3 and J H 4/J H 6 families were the most frequently observed.

show abstract

supporting

confidence: 82%

Use of V H, D and J H immunoglobulin gene segments in Brazilian patients with chronic lymphocytic leukaemia (CLL)

et al. 2008

View full text Add to dashboard Cite

show abstract

“…However, subpopulations of isotype class-switched cells often exist within the IgM þ IgD þ clone (32). CSR seems to occur independently of SHM, given that class-switch events predominate in U-CLL (33).…”

Section: Bcr Signaling Capacitymentioning

confidence: 99%

Immunogenetic Studies of Chronic Lymphocytic Leukemia: Revelations and Speculations about Ontogeny and Clinical Evolution

et al. 2014

View full text Add to dashboard Cite

Over the last decade, immunogenetic analysis of B-cell receptor immunoglobulins (BcR IG) has proved instrumental in dissecting chronic lymphocytic leukemia (CLL) pathogenesis. Initially, it was the finding that the level of somatic hypermutations in rearranged IG heavy-chain genes could define two CLL subtypes associated with a different clinical course that drew attention. As the years ensued, this not only continued to hold strong, but also revealed an unprecedented BcR restriction (aptly coined as "stereotypy"), thus cementing the idea that antigenic elements select the leukemic clones. With all this in mind, in the present review, we focus on the CLL BcR IG, a molecule that clearly lies at the heart of disease pathogenesis, and attempt to distil from past and emerging biologic knowledge the most relevant aspects in the context of the immunogenetics of CLL, while at the same time provoking questions that remain unanswered. We juxtapose CLL with mutated BcR IGs against CLL with unmutated BcR IGs due to their striking clinicobiologic differences; however, when considering ontogeny, common derivation of the two mutational subtypes cannot be excluded. The issue of stereotypy is intertwined throughout and we also raise the subject of isotype-switched CLL, which, despite its rarity, contributes intriguing ontogenetic hints. Cancer Res; 74(16); 4211-6. Ó2014 AACR.

show abstract

“…PCR amplification of different isotype transcripts was performed as described by Oppezzo et al 9 Circle isotype-specific (I-C) transcripts, termed circle transcripts (CTs), were analyzed by PCR with primers I-␥ (forward) and C-(reverse), as described by Kinoshita et al 11 Mutation analysis of V H and preswitch regions Sequences of V H genes were determined as previously described. 12 Mutations in the I/S region were studied by PCR using Taq High Fidelity polymerase (Roche Diagnostics, Mannheim, Germany) with the following primers: (A) 5Ј-GGC TGA CCG AAA CTG AAA AGG C-3Ј; and (D) 5Ј-GAA AGC TGG ATG AGT GTC ATG GCC-3Ј.…”

Section: Analysis Of Csr Processmentioning

confidence: 99%

Chronic lymphocytic leukemia B cells expressing AID display dissociation between class switch recombination and somatic hypermutation

Oppezzo

Vuillier

Vasconcelos

et al. 2003

Blood

109

View full text Add to dashboard Cite

IntroductionAfter gene rearrangement, immunoglobulin (Ig) variable genes are diversified by somatic hypermutation (SHM), whereas the effector function of the constant domain is modified by class switch recombination (CSR). These processes depend on activation-induced cytidine deaminase (AID), a putative RNA-editing enzyme expressed in B cells from secondary lymphoid organs on CD40 ligand (CD40L) stimulation. 1 Given that the absence of AID expression in one form of the hyper-IgM syndrome in humans 2 and in AID-targeted mice abolishes CSR and SHM, this protein is thought to play a major role in both processes. 3 Fifty percent of patients with chronic lymphocytic leukemia (CLL) display mutated V H genes. 4 The mutational profile of immunoglobulin genes represents an important prognostic factor 5,6 because patients expressing unmutated V H genes exhibit poor prognoses. In addition, previous reports 7-9 have demonstrated that CSR frequently occurs in CLL and predominates in unmutated B-cell CLLs (B-CLLs).In this work, we have examined the expression of AID transcripts, SHM, and CSR in 65 patients with CLL expressing either unmutated (33 of 65) or mutated (32 of 65) V H genes. Our results show that patients with unmutated B-CLL can constitutively express AID transcripts. This fact is associated with the presence of mutations in the preswitch DNA region and with an active CSR, but it is not related to the SHM process. Additionally, in patients with mutated CLL without constitutive AID expression, AID induction on stimulation results in preswitch mutations and the CSR process. Study design Healthy and CLL samplesBlood was collected from 4 healthy controls and 65 typical CLL patients from Hôtel-Dieu, Pitié-Salpêtrière, and Pasteur hospitals (Paris, France), Sao Paulo and Servidor Publico Estadual hospitals (Sao Paulo, Brazil), and Hospital Maciel (Montevideo, Uruguay). B cells were purified through negative depletion by using RosetteSep antibody cocktail (StemCell Technologies, Vancouver, BC, Canada) and were stimulated in vitro for 5 days with 1 g/mL recombinant soluble CD40L (Immunex, Seattle, WA) and 1000 U/mL interleukin (IL)-4 (PharMingen, San Diego, CA). Analysis of AID transcriptsPolymerase chain reaction (PCR) amplification of CLL cDNA was carried out as described previously, 2 and a semiquantitative protocol for AID expression was performed. Briefly, cDNA obtained from 5 ϫ 10 6 B cells was amplified by 20 cycles of PCR using AID 2 and GAPDH (glyceraldehyde-3-phosphate dehydrogenase) 10 primers. The fragments obtained were transferred and hybridized with specific AID and GAPDH ␣-[ 32 P] dCTP (deoxycytidine-5Ј-triphosphate)-labeled probes. Analysis of CSR processPCR amplification of different isotype transcripts was performed as described by Oppezzo et al. 9 Circle isotype-specific (I-C) transcripts, termed circle transcripts (CTs), were analyzed by PCR with primers I-␥ (forward) and C-(reverse), as described by Kinoshita et al. 11 Mutation analysis of V H and preswitch regions Sequences of V H genes were det...

show abstract

Do CLL B cells correspond to naive or memory B-lymphocytes? Evidence for an active Ig switch unrelated to phenotype expression and Ig mutational pattern in B-CLL cells

Abstract: Recent work suggests that chronic lymphocytic leukemia (B-CLL

Cited by 38 publications

References 46 publications

Use of V H, D and J H immunoglobulin gene segments in Brazilian patients with chronic lymphocytic leukaemia (CLL)

Use of V H, D and J H immunoglobulin gene segments in Brazilian patients with chronic lymphocytic leukaemia (CLL)

Immunogenetic Studies of Chronic Lymphocytic Leukemia: Revelations and Speculations about Ontogeny and Clinical Evolution

Chronic lymphocytic leukemia B cells expressing AID display dissociation between class switch recombination and somatic hypermutation

Contact Info

Product

Resources

About