Agricultural Pesticide Use  and the T(14;18) Connection to Lymphomagenesis

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 375-375
Author(s):  
Sandrine Roulland ◽  
Julie Agopian ◽  
Yannick Lecluse ◽  
Jean-Marc Navarro ◽  
Anne-claire Gac ◽  
...  
Keyword(s):  
B Cells ◽  
Pesticide Exposure ◽  
Somatic Hypermutation ◽  
Clonal Evolution ◽  
Surface Expression ◽  
Malignant Progression ◽  
Pesticide Use ◽  
Agricultural Pesticide ◽  
Non Hodgkin Lymphoma ◽  
The Status

Abstract Agricultural pesticide use has been repeatedly, but not consistently, associated with risk of non-Hodgkin lymphoma (NHL). Over the past years, it has become clear that NHL heterogeneity is setting many hurdles to this connection and that pertinent bio-markers must be identified according to malignant subtypes. Among those, t(14;18) translocation constitutes the early and promoting event of a cascade of causative effects leading to Follicular Lymphoma (FL): ectopic BCL2 expression leads to the rescue, accumulation, and developmental block of germinal center (GC) B-cells; there, protracted AID activity would favor the occurrence of complementary oncogenic hits and malignant progression, which arise from mistakes during somatic hypermutation (SHM) and class-switch recombination (CSR) processes. Although the significance of t(14;18) in blood from healthy individuals is yet unclear, evidence for a higher prevalence has been reported among farmers occupationally exposed to pesticides. Furthermore, recent findings have established that pesticide exposure is significantly associated with risk of t(14;18)+ NHL but not with t(14;18)-negative cases, suggesting that pesticides may act through a t(14;18)-dependant pathway. To get molecular insights into this connection, we followed and compared the status and clonal evolution of t(14;18)+ cells over a median of 9 years in blood samples issued from a cohort of farmers exposed to pesticides (n=112) with those of non-farmer controls (n=25). We report here that exposed individuals exhibit a much higher increase of t(14;18) frequency in blood, and that this increase result far less from a genotoxic effect of pesticides than from an immunogenic effect leading to an extensive clonal expansion of activated t(14;18)+ B cells. Strikingly, we demonstrate that such clones recapitulate the hallmark features of developmentally blocked FL cells as they 1) express high levels of BCL2/JH fusion transcripts; 2) retain the CD10 surface expression normally lost upon GC exit; and 3) sustain constitutive AID activity with the most advanced ones bearing, unexpectedly, early stigmata of AID-mediated genomic instability. Altogether these results show that expanded t(14;18)+ clones in farmers exposed to pesticides constitute bona fide FL precursors standing at various stages of tumor progression and support the notion of a direct connection between t(14;18) frequency in blood and malignant progression that could be could helpful in the identification of individuals at “high” risk for transformation to overt FL.

scholarly journals Agricultural pesticide exposure and the molecular connection to lymphomagenesis

2009 ◽  
Vol 206 (7) ◽  
pp. 1473-1483 ◽  
Author(s):  
Julie Agopian ◽  
Jean-Marc Navarro ◽  
Anne-Claire Gac ◽  
Yannick Lecluse ◽  
Mélanie Briand ◽  
...  
Keyword(s):  
Pesticide Exposure ◽  
Cytidine Deaminase ◽  
Clonal Evolution ◽  
Malignant Progression ◽  
Healthy Individuals ◽  
Agricultural Pesticide ◽  
Cytidine Deaminase Activity ◽  
Activation Induced Cytidine Deaminase ◽  
Bona Fide ◽  
Clonal Progression

The t(14;18) translocation constitutes the initiating event of a causative cascade leading to follicular lymphoma (FL). t(14;18) translocations are present in blood from healthy individuals, but there is a trend of increased prevalence in farmers exposed to pesticides, a group recently associated with higher risk of t(14;18)+ non-Hodgkin's lymphoma development. A direct connection between agricultural pesticide use, t(14;18) in blood, and malignant progression, however, has not yet been demonstrated. We followed t(14;18) clonal evolution over 9 yr in a cohort of farmers exposed to pesticides. We show that exposed individuals bear particularly high t(14;18) frequencies in blood because of a dramatic clonal expansion of activated t(14;18)+ B cells. We further demonstrate that such t(14;18)+ clones recapitulate the hallmark features of developmentally blocked FL cells, with some displaying aberrant activation-induced cytidine deaminase activity linked to malignant progression. Collectively, our data establish that expanded t(14;18)+ clones constitute bona fide precursors at various stages of FL development, and provide a molecular connection between agricultural pesticide exposure, t(14;18) frequency in blood, and clonal progression.

scholarly journals Distinct Recirculating and Non-Recirculating B-Lymphocyte Pools in the Peripheral Blood Are Defined by Coordinated Expression of CD21 and L-Selectin

Blood ◽  
1997 ◽  
Vol 90 (12) ◽  
pp. 4865-4875 ◽  
Author(s):  
Alan J. Young ◽  
Wendy L. Marston ◽  
Mark Dessing ◽  
Lisbeth Dudler ◽  
Wayne R. Hein
Keyword(s):  
B Cells ◽  
Peripheral Blood ◽  
B Lymphocyte ◽  
Surface Expression ◽  
Peripheral Blood Lymphocytes ◽  
Phenotypic Analysis ◽  
Phenotypic Properties ◽  
Blood Lymphocytes ◽  
The Status ◽  
Coordinated Expression

Abstract The continual recirculation of lymphocytes between the blood, tissues, and lymph is essential for the coordination and dissemination of immune responses. We have compared the functional and phenotypic properties of lymphocytes isolated from blood and lymph, the two major migratory populations. Lymph-borne lymphocytes migrated readily into the lymphatic recirculation pathway, but greater than one third of all peripheral blood lymphocytes (PBLs) were excluded from the lymphatic circuit and showed an enhanced migration to the spleen. Phenotypic analysis showed that most non-recirculating PBLs were B cells. The migration competence of B cells correlated with the surface expression of CD21 and L-selectin; recirculating B cells expressed both of these molecules, whereas non-recirculating B cells lacked both antigens. These results establish that blood contains distinct pools of lymphocytes that differ in their recirculation competence. Clearly, blood sampling is not an efficient method to directly measure the status of the recirculating immune system, and implies important constraints and restrictions in the interpretation of experimental or clinical data that include phenotypic and quantitative analyses of blood lymphocytes.

Long-Term Clonal Evolution of Circulating Follicular Lymphoma-Like B Cells in Healthy Individuals: An Early Pathway to Lymphomagenesis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 185-185 ◽  
Author(s):  
Sandrine Roulland ◽  
Julie Agopian ◽  
Mélanie Briand ◽  
Jean-Marc Navarro ◽  
Yannick Lecluse ◽  
...  
Keyword(s):  
B Cells ◽  
Follicular Lymphoma ◽  
Somatic Hypermutation ◽  
Clonal Evolution ◽  
Low Frequency ◽  
Memory B Cells ◽  
Healthy Individuals ◽  
Parallel Acquisition ◽  
Expanding Population ◽  
Over Time

Abstract Follicular lymphoma (FL), one of the most common B cell non-Hodgkin’s lymphoma, is a germinal centre (GC)-derived malignancy, for which acquisition of the oncogenic t(14;18) translocation in the bone marrow constitute the genetic hallmark and early initiating event of FL pathogenesis. As t(14;18) is also present at low frequency in peripheral blood from healthy individuals (HI), it has been assumed that in HI, t(14;18) is carried by circulating quiescent naïve B-cells with restrained oncogenic potential. In sharp contrast, we recently demonstrated that in HI, t(14;18) is mainly carried by an expanding population of atypical B-cells presumably issued from the GC, displaying genotypic and phenotypic features of FL, and prone to constitute potent pre-malignant niches. Based on these data, we proposed that in HI, most t(14;18)+ cells were similarly rescued by BCL2 from apoptosis, and “frozen” at a differentiation stage where constitutive AID expression drives continuous somatic hypermutation (SHM) and class switch recombination (CSR) activity, two GC-associated mechanisms conferring a high propensity for further oncogenic aberrations. To test this model, we investigated the evolution of t(14;18)+ clones over time in HI by examining whether “FL-like” clonal development is associated with GC-specific processes. Using immunophenotypic, LR-PCR and mutation pattern analysis of the upstream switch μ flanking region from the translocated allele, we found that most circulating FL-like cells retain the GC-specific CD10 marker and carry highly mutated Sμ regions with a similar pattern to the mutated IgV genes, signing the maintenance of a GC-derived AID-mediated process. Moreover, as found for FL clones, the mutation load is higher in isotype switched than in sIgM+ t(14;18)+ cells, a difference maintained during the course of evolution (parallel acquisition of CSR/SHM on both functional and translocated alleles). We next analyzed intraclonal variation (ICV) as a way to determine how t(14;18)+ clones evolve over time based on their common BCL2/JH signature. In contrast to typical GC-derived memory B cells, which usually undergo transitory and extensive proliferation upon antigenic challenge without further SHM, we were able to construct genealogical trees for most circulating t(14;18)+ clones. Interestingly, few t(14;18)+ clones, although persistent and frequent, showed no clear evidence for clonal evolution but rather subclone selection. The presence of ICV and most importantly the identification of a somatically mutated common precursor through clonal arborescence confirm that FL-like cells not only display a GC-”frozen” phenotype but also provide direct support for the existence of premalignant niches from which cells undergo clonal evolution/selection and are constantly released. Although it remains currently unknown whether t(14;18)+ clones are directly issued from the GC founder or, similarly to FL, acquired the ability to invade other reactive GC for further rounds of SHM/CSR, ICV constitute an indirect signature for intense dynamics of the cells. Taken together, our results indicate that long-lived t(14;18)+ cells from HI are not conventional memory B-cells but recapitulate features of a “frozen” GC-derived population, able to undergo active AID-mediated processes while retaining at the same time dependence on BCR expression and presumably keeping the potential for intense trafficking between blood and tissues, a unique feature shared with FL cells.

scholarly journals Distinct clonal evolution of B-cells in HIV controllers with neutralizing antibody breadth

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Deniz Cizmeci ◽  
Giuseppe Lofano ◽  
Evan Rossignol ◽  
Anne-Sophie Dugast ◽  
Dongkyoon Kim ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Somatic Hypermutation ◽  
Clonal Evolution ◽  
Neutralizing Antibody ◽  
Affinity Maturation ◽  
Gene Repertoire ◽  
Immunoglobulin Gene ◽  
Hiv Controllers ◽  
Hiv 1

A minor subset of individuals infected with HIV-1 develop antibody neutralization breadth during the natural course of the infection, often linked to chronic, high-level viremia. Despite significant efforts, vaccination strategies have been unable to induce similar neutralization breadth and the mechanisms underlying neutralizing antibody induction remain largely elusive. Broadly neutralizing antibody responses can also be found in individuals who control HIV to low and even undetectable plasma levels in the absence of antiretroviral therapy, suggesting that high antigen exposure is not a strict requirement for neutralization breadth. We therefore performed an analysis of paired heavy and light chain B-cell receptor (BCR) repertoires in 12,591 HIV-1 envelope-specific single memory B-cells to determine alterations in the BCR immunoglobulin gene repertoire and B-cell clonal expansions that associate with neutralizing antibody breadth in 22 HIV controllers. We found that the frequency of genomic mutations in IGHV and IGLV was directly correlated with serum neutralization breadth. The repertoire of the most mutated antibodies was dominated by a small number of large clones with evolutionary signatures suggesting that these clones had reached peak affinity maturation. These data demonstrate that even in the setting of low plasma HIV antigenemia, similar to what a vaccine can potentially achieve, BCR selection for extended somatic hypermutation and clonal evolution can occur in some individuals suggesting that host-specific factors might be involved that could be targeted with future vaccine strategies.

IGH Repertoire Analysis In Multiple Myeloma (MM): Lack of Intra-Disease Homology and Occasional Clustering with Sequences of Other B-Cell Neoplasms Sharing Identical Geographical Origin

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2951-2951
Author(s):  
Simone Ferrero ◽  
Daniela Capello ◽  
Mirija Svaldi ◽  
Daniela Drandi ◽  
Michela Boi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
B Cells ◽  
B Cell ◽  
B Lymphocyte ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Somatic Hypermutation ◽  
Cell Repertoire ◽  
Non Hodgkin Lymphoma ◽  
B Cell Subsets

Abstract Abstract 2951 Background: The identification of stereotyped immunoglobulin (IG) receptors has improved our knowledge on the pathogenesis of several B-cell malignancies, suggesting the role of antigen-driven stimulation in chronic lymphocitic leukemia (CLL), marginal-zone lymphoma (MZL) and mantle-cell lymphoma (MCL). Multiple myeloma (MM) is a terminally-differentiated neoplasm no longer expressing surface IG; however some reports suggest the existence of early B-lymphocyte precursors which could be susceptible to antigen-driven stimulation. IG heavy chain (IGH) repertoire has not been extensively investigated in MM, with the largest available reports containing less than 80 complete sequences. Aims: To address this issue we created a database of MM IGH sequences including our institutional records (mostly derived from minimal residual disease studies) and sequences available from the literature. We planned a two-step analysis: a) first we characterized the MM repertoire and performed intra-MM clustering analysis; b) then we compared our MM series to a large public database of IGH sequences from neoplastic and non-neoplastic B-cells in search of similarities between MM sequences and other normal or neoplastic IGH repertoires. Patients and methods: 131 MM IGH genes were amplified and sequenced at our Institutions and belonged to Italian patients, while 214 MM IGH sequences from non-Italian patients were derived from published databases (NCBI-EMBL-IMGT/LIGM-DB) for a total of 345 fully interpretable MM sequences (out of 396). 28590 IGH sequences from other malignant and non-malignant B-cells were retrieved from the same public databases, including approximately 4500 CLL/Non-Hodgkin lymphoma (NHL) sequences and comprising 500 sequences from Italian patients. All sequences were analyzed using the IMGT database and tools (Lefranc et al., Nucleic Acid Res. 2005; http://imgt.cines.fr/) to identify IGHV-D-J gene usage, to assess the somatic hypermutation (SHM) rate and to identify HCDR3. HCDR3 aminoacidic sequences were aligned together using the ClustalX 2.0 software (Larkin et al., Bioinformatics, 2007; http://www.clustal.org/). Subsets of stereotyped IGH receptors were defined according to Stamatopoulos et al. (Blood, 2007). Result: IGHV analysis in MM was almost in keeping with the normal B-cell repertoire, showing a less remarkably biased IGH usage compared to CLL, MCL and MZL (with seven genes accounting for 40% of cases, compared to respectively five, three and two genes). However, a modest but significant over-representation of IGHV1-69, 2–5, 2–70, 3–21, 3–30-3, 3–43, 5–51 and 6-1 genes and under-representation of the IGHV1-18, 1–8, 3–30, 3–53 and 4–34 was noticed. The rate of somatic hypermutation in MM followed a Gaussian distribution with a median value of 7.8%. Intra-MM search for HCDR3 similarities never met minimal requirements for stereotyped receptors. When MM sequences were compared to non-MM database, only a minority of MM sequences (2.6%, n=9) clustered with sequences from lymphoid tumors and normal B-cells (figure 1A). In particular two non-Italian MM sequences clustered with previously characterized, uncommon CLL subsets (n.37 and n.71 according to Murray et al., Blood 2008). Moreover, novel provisional clusters were observed including three MM-CLL subsets, one MM-NHL subset, and three MM-normal B-cell subsets. While the MM-normal B-cell clusters involved non-Italian patients, we unexpectedly noticed that the four MM-CLL/MM-NHL clusters were composed exclusively of Italian patients, as shown in figure 1B, although Italian subjects represented less than 12% of the entire CLL-NHL database. Conclusion: The analysis of the largest currently available database of MM IGH sequences indicates the following: 1) MM IGH repertoire is closer to physiological distribution than that of CLL, MCL and MZL; 2) MM specific clusters do not occur to a frequency detectable with currently available databases; 3) 98% of MM sequences are not related to other “highly-clustered” lymphoproliferative disorders; 4) Uncommon clustering phenomena may follow a geographical rather than a disease-related pattern. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Distinct Recirculating and Non-Recirculating B-Lymphocyte Pools in the Peripheral Blood Are Defined by Coordinated Expression of CD21 and L-Selectin

Blood ◽  
1997 ◽  
Vol 90 (12) ◽  
pp. 4865-4875
Author(s):  
Alan J. Young ◽  
Wendy L. Marston ◽  
Mark Dessing ◽  
Lisbeth Dudler ◽  
Wayne R. Hein
Keyword(s):  
B Cells ◽  
Peripheral Blood ◽  
B Lymphocyte ◽  
Surface Expression ◽  
Peripheral Blood Lymphocytes ◽  
Phenotypic Analysis ◽  
Phenotypic Properties ◽  
Blood Lymphocytes ◽  
The Status ◽  
Coordinated Expression

The continual recirculation of lymphocytes between the blood, tissues, and lymph is essential for the coordination and dissemination of immune responses. We have compared the functional and phenotypic properties of lymphocytes isolated from blood and lymph, the two major migratory populations. Lymph-borne lymphocytes migrated readily into the lymphatic recirculation pathway, but greater than one third of all peripheral blood lymphocytes (PBLs) were excluded from the lymphatic circuit and showed an enhanced migration to the spleen. Phenotypic analysis showed that most non-recirculating PBLs were B cells. The migration competence of B cells correlated with the surface expression of CD21 and L-selectin; recirculating B cells expressed both of these molecules, whereas non-recirculating B cells lacked both antigens. These results establish that blood contains distinct pools of lymphocytes that differ in their recirculation competence. Clearly, blood sampling is not an efficient method to directly measure the status of the recirculating immune system, and implies important constraints and restrictions in the interpretation of experimental or clinical data that include phenotypic and quantitative analyses of blood lymphocytes.

scholarly journals Effect of Pesticide Exposure on Non-Hodgkin Lymphoma Incidence and Survival in California

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 5006-5006
Author(s):  
Christina Poh ◽  
John D. McPherson ◽  
Joseph Tuscano ◽  
Qian Li ◽  
Arti Parikh-Patel ◽  
...  
Keyword(s):  
Land Use ◽  
Overall Survival ◽  
Hodgkin Lymphoma ◽  
Census Tract ◽  
Research Funding ◽  
Pesticide Exposure ◽  
Pesticide Use ◽  
Non Hodgkin Lymphoma ◽  
California Cancer Registry ◽  
The Impact

Abstract Introduction: While previous studies propose pesticide exposure to be a risk factor for non-Hodgkin lymphoma (NHL) development, results are inconclusive. In addition, the impact of pesticide exposure on NHL survival is not well-established. Therefore, we identified NHL patients from the California Cancer Registry and linked these patients with the statewide pesticide use reporting database to determine the impact of pesticide exposure on NHL-related incidence and outcomes. Methods: Using the California Cancer Registry, we identified patients with a first primary diagnosis of NHL from 2010-2016 and linked these patients with CalEnviroScreen 3.0 to obtain production agriculture pesticide exposure to 70 chemicals from the state mandated Pesticide Use Reporting (PUR) by census tract from 2012-2014. In addition, data from PUR was integrated into a geographic information system that employs land use data to estimate cumulative exposure to specific pesticides previously associated with NHL (glyphosate, organophosphorus, carbamate, phenoxyherbicide and 2,4-dimethylamine salt) between 10 years prior up to 1 year after NHL diagnosis. SEER*Stat software was used to calculate NHL subtype incidence rates by census tract pesticide use level. Multivariable cox proportional hazards regression models were used to evaluate the impact of total pesticide exposure from CalEnviroScreen 3.0 and individual pesticide exposure from geographic land use data on lymphoma-specific and overall survival. Results: Among 35,808 NHL patients identified, 44.2% were exposed to pesticide in their census tract of residence. Pesticide exposure was higher in Hispanic/Latino (46.5%) and non-Hispanic white (45.6%) then Asian/Pacific Islander (37.2%) and African American (34.9%) patients with NHL. Glyphosate, organophosphorus, carbamate, phenoxyherbicide and 2,4-dimethylamine salt exposure was reported in 34.1%, 26.0%, 10.6%, 14.0% and 12.8% of NHL patients, respectively. Pesticide exposure was not associated with increased NHL incidence by NHL subtype or subgroups defined by sociodemographic factors. Total pesticide exposure at time of diagnosis was not associated with lymphoma-specific or overall survival. In addition, no association was consistently found between glyphosate, organophosphorus, carbamate, phenoxyherbicide and 2,4 dimethylamine salt exposure and lymphoma-specific or overall survival. Conclusion: In this large population-based study of neighborhood agricultural pesticide exposure, pesticide exposure was noted to be prevalent among patients diagnosed with NHL, with high pesticide exposure particularly observed in Hispanics/Latinos and non-Hispanic whites. However, pesticide exposure was not consistently associated with increased NHL incidence or worse NHL lymphoma-specific or overall survival. Disclosures Poh: Acrotech: Honoraria; Incyte: Research Funding; Morphosys: Consultancy. Tuscano: BMS: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding; Acrotech: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding.

Mechanisms of Clonal Evolution of Pre-Leukemic Clones in Childhood Pre-B Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 861-861
Author(s):  
Srividya Swaminathan ◽  
Lars Klemm ◽  
Eugene Park ◽  
Anthony M Ford ◽  
Soo-mi Kweon ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Somatic Hypermutation ◽  
Fetal Liver ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Childhood All ◽  
Class Switch ◽  
Cell Clones ◽  
Inflammatory Stimuli

Abstract Background and hypothesis: Childhood pre-B acute lymphoblastic leukemia (ALL) can frequently be retraced to a pre-leukemic clone carrying a prenatally acquired genetic lesion (e.g. ETV6-RUNX1gene rearrangement). After birth, pre-leukemic clones can acquire secondary mutations and, hence, evolve towards overt leukemia. While this concept is well established, the mechanism(s) driving clonal evolution are not known. Epidemiological findings hint to a role of delayed childhood infections and chronic inflammation as etiologic factors of childhood ALL, but do not illuminate mechanism of clonal evolution of pre-leukemic cells. In this study, we demonstrate that cooperation between the AID cytosine deaminase and the RAG1/RAG2 V(D)J recombinase promotes acquisition of secondary genetic lesions that promote progress of pre-leukemic B cell precursors towards full-blown leukemia. Results: The enzymatic activity of RAG1/RAG2 (VDJ recombination) and AID (somatic hypermutation, class-switch recombination) are strictly segregated to early and late stages of B cell development, respectively. While RAG1 and RAG2 are actively expressed at stages of early B cell development (bone marrow and fetal liver) that give rise to pre-B ALL, little is known about the function of AID in early B-lymphopoesis. As the involvement of AID in pre-B leukemic clonal evolution is incumbent on its expression during early stages of B-lymphopoesis, we tested CD19+ pre-B cells isolated from human bone marrow (BM) for indicators of AID activity, namely, somatic hypermutation (SHM) and class switch recombination (CSR). Interestingly, most pre-B cell clones carry rearranged Ig VH region genes that are mutated at low levels (average mutation frequency 26 x 10-3 bp). Likewise, pre-B cells isolated from fetal liver tissues (three donors; 10-19 weeks of gestation) carried Ig VH region genes mutated at low levels (average mutation frequency 14 x 10-3 bp). In addition, about one third of fetal liver pre-B cells had undergone CSR to Cγ3, Cγ1 and Cα regions. These findings highlight the previously unknown function of AID in two important sites of early human B-lymphopoesis. Based on these results, we hypothesized that a specific B cell subset during early pro- and pre-B cell differentiation can concomitantly express both AID and the RAGs and, hence, would be particularly susceptible to clonal evolution of cells that carry a pre-leukemic lesion. Our subsequent studies identified late pre-B cells (Fraction D) as a natural subset of increased genetic vulnerability. Late pre-B cells downregulate IL7 receptor/Stat5 signaling, which enables expression of RAG1 and RAG2 and immunoglobulin light chain gene rearrangement. Loss of IL7 receptor/Stat5 signaling also removes an important safeguard against premature expression of AID. Therefore, late pre-B cells are poised to express AID at high levels in response to inflammatory stimuli (e.g. LPS) in concurrence with RAG1 and RAG2. Studying clonal evolution of patient-derived pre-B ALL cells, we found evidence for concomitant AID and RAG1/RAG2 activity. Further studying a genetic mouse model for pre-leukemic pre-B cells carrying ETV6-RUNX1, we found that repeated exposure to LPS can cause overt leukemia but not in the absence of either AID or Rag1. Additionally, whole exome sequencing of human B cell clones that were engineered to express AID, RAG1/RAG2 alone or in combination revealed that concurrent expression of AID with RAG1/RAG2 dramatically increased the frequency of structural chromosomal lesions. Conclusion: Consistent with epidemiological findings on the etiology of childhood ALL, we conclude that reduced cytokine signaling (here, IL7R) in late pre-B cells renders pre-leukemic clones distinctively vulnerable to genetic lesions that can be acquired in the context of repeated exposure to inflammatory stimuli (e.g. chronic and recurrent infections during childhood). Our results support a role for AID and RAGs cooperation for the generation of secondary lesions in leukemia subgroups that require additional leukemogenic events, and therefore, provide the genetic and molecular basis to support the Delayed Infections Hypothesis for leukemia progression in children. Disclosures No relevant conflicts of interest to declare.

scholarly journals Distinct clonal evolution of B-cells in HIV controllers with neutralizing antibody breadth

2020 ◽  
Author(s):  
Deniz Cizmeci ◽  
Giuseppe Lofano ◽  
Anne-Sophie Dugast ◽  
Dongkyoon Kim ◽  
Guy Cavet ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Somatic Hypermutation ◽  
Clonal Evolution ◽  
Neutralizing Antibody ◽  
Affinity Maturation ◽  
Gene Repertoire ◽  
Immunoglobulin Gene ◽  
Hiv Controllers ◽  
Hiv 1

AbstractA minor subset of individuals infected with HIV-1 develop antibody neutralization breadth during the natural course of the infection, often linked to chronic, high level viremia. Despite significant efforts, vaccination strategies have been unable to induce similar neutralization breadth and the mechanisms underlying neutralizing antibody induction remain largely elusive. Broadly neutralizing antibody responses can also be found in individuals who control HIV to low and even undetectable plasma levels in the absence of antiretroviral therapy, suggesting that high antigen exposure is not a strict requirement for neutralization breadth. We therefore performed an analysis of paired heavy and light chain B-cell receptor repertoires in 12,591 HIV-1 Envelope-specific single memory B-cells to determine alterations in the BCR immunoglobulin gene repertoire and B-cell clonal expansions that associate with neutralizing antibody breadth in 22 HIV controllers. We found that the frequency of genomic mutations in IGHV and IGLV was directly correlated with serum neutralization breadth. The repertoire of the most mutated antibodies was dominated by a small number of large clones with evolutionary signatures suggesting that these clones had reached peak affinity maturation. These data demonstrate that even in the setting of low plasma HIV antigenemia, similar to what a vaccine can potentially achieve, BCR selection for extended somatic hypermutation and clonal evolution can occur in some individuals suggesting that host-specific factors might be involved that could be targeted with future vaccine strategies.

Sign in / Sign up

Export Citation Format

Share Document