The IgH Locus 3′ Regulatory Region

Pinaud, Eric; Marquet, Marie; Fiancette, Rémi; Péron, Sophie; Vincent-Fabert, Christelle; Denizot, Yves; Cogné, Michel

doi:10.1016/b978-0-12-387663-8.00002-8

Cited by 114 publications

(89 citation statements)

References 274 publications

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“…13,26 However, IgH-3'RRs also regulates IgH expression, somatic hypermutation and class switch in the wild-type IgH allele. 27, 28, 29, 30, 31 Therefore, we reasoned that intratumoral heterogeneity of BCL2 expression in lymphoma cells should at least in part originate from differential mRNA transcription from the t(14;18)-translocated allele, and correlate with IgH since both are controlled by IgH-3'RRs regions. To analyze the BCL2 and IgH mRNA transcripts in single lymphoma cells, we implemented an smFISH technique that allows absolute measurements of the number of mRNA molecules in individual cells.…”

Section: Resultsmentioning

confidence: 99%

Inter- and intratumoral heterogeneity of BCL2 correlates with IgH expression and prognosis in follicular lymphoma

Barreca

Martinengo

Annaratone

et al. 2014

Blood Cancer Journal

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Most follicular lymphomas (FLs) are genetically defined by the t(14;18)(q32;q21) translocation that juxtaposes the BCL2 gene to the immunoglobulin heavy chain (IgH) 3' regulatory regions (IgH-3'RRs). Despite this recurrent translocation, FL cases are heterogeneous in terms of intratumoral clonal diversity for acquired mutations and variations in the tumor microenvironment. Here we describe an additional mechanism that contributes to inter- and intratumoral heterogeneity in FLs. By applying a novel single-molecule RNA fluorescence-based in situ hybridization (FISH) technique to detect mRNA molecules of BCL2 and IgH in single cells, we found marked heterogeneity in the number of BCL2 mRNA transcripts within individual lymphoma cells. Moreover, BCL2 mRNA molecules correlated with IgH mRNA molecules in individual cells both in t(14;18) lymphoma cell lines and in patient samples. Consistently, a strong correlation between BCL2 and IgH protein levels was found in a series of 205 primary FL cases by flow cytometry and immunohistochemistry. Inter- and intratumoral heterogeneity of BCL2 expression determined resistance to drugs commonly used in FL treatment and affected overall survival of FL patients. These data demonstrate that BCL2 and IgH expressions are heterogeneous and coregulated in t(14;18)-translocated cells, and determine the response to therapy in FL patients.

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Section: Resultsmentioning

confidence: 99%

Inter- and intratumoral heterogeneity of BCL2 correlates with IgH expression and prognosis in follicular lymphoma

Barreca

Martinengo

Annaratone

et al. 2014

Blood Cancer Journal

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“…Ig enhancers, which are known transcriptional regulators (13, 82), promote SHM within transgenic V(D)J substrates (84, 86, 87). However, such enhancers, including the IgH intronic enhancer (iEμ), intronic Igκ enhancer (iEκ) and 3′ Igκ enhancer were deleted in mice and found to not be required for SHM (87, 88, 89).…”

Section: Somatic Hypermutationmentioning

confidence: 99%

“…IgM, IgG, IgE, IgA). Within the IgH locus, there are several B cell specific enhancers, for example iEμ, which lies between the J H segments and the Cμ exons and a 30 kb IgH 3′ regulatory region (“IgH 3′RR”), which is downstream of the Cα exons (11, 13) (Fig. 2a).…”

Section: Overview and Introductionmentioning

confidence: 99%

Related Mechanisms of Antibody Somatic Hypermutation and Class Switch Recombination

2015

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The primary antibody repertoire is generated by mechanisms involving the assembly of the exons that encode the antigen-binding variable regions of immunoglobulin heavy (IgH) and light (IgL) chains during the early development of B lymphocytes. After antigen-dependent activation, mature B lymphocytes can further alter their IgH and IgL variable region exons by the process of somatic hypermutation (SHM), which allows the selection of B cells in which SHMs resulted in the production of antibodies with increased antigen affinity. In addition, during antigen-dependent activation, B cells can also change the constant region of their IgH chain through a DNA double-strand-break (DSB) dependent process referred to as IgH class switch recombination (CSR), which generates B cell progeny that produce antibodies with different IgH constant region effector functions that are best suited for a elimination of a particular pathogen or in a particular setting. Both the mutations that underlie SHM and the DSBs that underlie CSR are initiated in target genes by activation-induced cytidine deaminase (AID). This review describes in depth the processes of SHM and CSR with a focus on mechanisms that direct AID cytidine deamination in activated B cells and mechanisms that promote the differential outcomes of such cytidine deamination.

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“…The 3′ regulatory region at the 3′ of the Ig α -1 constant gene includes three enhancers among which only the central HS1,2-A is polymorphic (see Figure 1) [9]. This region is involved in B lymphocytes maturation and Ig production [10].…”

Section: Introductionmentioning

confidence: 99%

HS1,2 Ig Enhancer Alleles Association to AIDS Progression in a Pediatric Cohort Infected with a Monophyletic HIV-Strain

Montesano

Giambra

Frezza

et al. 2014

BioMed Research International

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Alteration in the humoral immune response has been observed during HIV infection. The polymorphisms of enhancer HS1,2, member of the 3′ regulatory region of the Ig heavy chain cluster, may play a role in the variation of the humoral response leading to pathological conditions. To assess the role of the HS1,2 polymorphic variants in the progression of AIDS, the HS1,2-A allelic frequencies were investigated in a cohort of HIV infected pediatric subjects from a nosocomial outbreak with a monophyletic strain of HIV. From a total group of 418 HIV infected children in the outbreak cohort, 42 nonprogressors and 31 progressors without bias due to antiretroviral therapy were evaluated. HS1,2 allele ∗1 has been associated with nonprogressors (allelic frequency: 51.19% versus 33.87% in progressors, OR 0.5, and P = 0.0437), while allele ∗2 has been associated with progression (allelic frequency: 48.39% versus 30.95% in nonprogressors, OR 2.1, and P = 0.0393). Further, only subjects carrying allele ∗2 in absence of allele ∗1, either in homozygous condition for allele ∗2 [nonprogressors 2/42 (4.76%), Progressors 7/31 (22.58%), OR 5.8, and P = 0.0315] or in combination with other allelic variants [nonprogressors 7/42 (16.67%), Progressors 13/31 (41.93%), OR 3.61, and P = 0.0321], have been associated with HIV progression to AIDS. In conclusion, while the HS1,2 allele ∗1 has a protective effect on HIV progression when present, allele ∗2 is associated with progression toward AIDS when allele ∗1 is absent.

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The IgH Locus 3′ Regulatory Region

Cited by 114 publications

References 274 publications

Inter- and intratumoral heterogeneity of BCL2 correlates with IgH expression and prognosis in follicular lymphoma

Inter- and intratumoral heterogeneity of BCL2 correlates with IgH expression and prognosis in follicular lymphoma

Related Mechanisms of Antibody Somatic Hypermutation and Class Switch Recombination

HS1,2 Ig Enhancer Alleles Association to AIDS Progression in a Pediatric Cohort Infected with a Monophyletic HIV-Strain

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