AID in Chronic Lymphocytic Leukemia: Induction and Action During Disease Progression

Oppezzo, Pablo; Navarrete, Marcelo A.; Chiorazzi, Nicholas

doi:10.3389/fonc.2021.634383

Cited by 17 publications

(12 citation statements)

References 239 publications

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“…We speculate that in vaccinated individuals with LY and MM, following only two exposures to the spike protein, the affinity maturation of memory B cells may be accelerated or the breadth of antibodies may be expanded by yet undefined mechanisms. In hematologic malignancies, a deregulation and constitutive expression or activation of proteins of the apolipoprotein B mRNA-editing enzyme catalytic polypeptide (APOBEC) family of deaminases, which are involved in oncogenesis, has been reported [56][57][58][59][60][61] . Canonical functions of these types of enzymes, particularly activation-induced cytidine deaminase (AID), are key to somatic hypermutation in B cells and thus the generation of high-affinity antibodies.…”

Section: Nature Cancermentioning

confidence: 99%

Potent high-avidity neutralizing antibodies and T cell responses after COVID-19 vaccination in individuals with B cell lymphoma and multiple myeloma

et al. 2022

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Individuals with hematologic malignancies are at increased risk for severe coronavirus disease 2019 (COVID-19), yet profound analyses of COVID-19 vaccine-induced immunity are scarce. Here we present an observational study with expanded methodological analysis of a longitudinal, primarily BNT162b2 mRNA-vaccinated cohort of 60 infection-naive individuals with B cell lymphomas and multiple myeloma. We show that many of these individuals, despite markedly lower anti-spike IgG titers, rapidly develop potent infection neutralization capacities against several severe acute respiratory syndrome coronavirus 2 variants of concern (VoCs). The observed increased neutralization capacity per anti-spike antibody unit was paralleled by an early step increase in antibody avidity between the second and third vaccination. All individuals with hematologic malignancies, including those depleted of B cells and individuals with multiple myeloma, exhibited a robust T cell response to peptides derived from the spike protein of VoCs Delta and Omicron (BA.1). Consistently, breakthrough infections were mainly of mild to moderate severity. We conclude that COVID-19 vaccination can induce broad antiviral immunity including ultrapotent neutralizing antibodies with high avidity in different hematologic malignancies.

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Section: Nature Cancermentioning

confidence: 99%

Potent high-avidity neutralizing antibodies and T cell responses after COVID-19 vaccination in individuals with B cell lymphoma and multiple myeloma

et al. 2022

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“…Prompted by the high rate of aberrant somatic hypermutation of BCL2 in aggressive lymphomas 21 and the fact that DNA damage was among the top-enriched processes by GREAT, we next investigated possible links between the expression levels of TAp63 and AICDA, the gene encoding the activation-induced (cytidine) deaminase enzyme that catalyzes somatic hypermutation; 22 however, we failed to document any significant correlation (supplemental Figure 4).…”

Section: Resultsmentioning

confidence: 98%

The TΑp63/BCL2 axis represents a novel mechanism of clinical aggressiveness in chronic lymphocytic leukemia

et al. 2022

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The TA-isoform of the p63 transcription factor (TAp63) has been reported to contribute to clinical aggressiveness in chronic lymphocytic leukemia (CLL) in a hitherto elusive way. Here, we sought to further understand and define the role of TAp63 in the pathophysiology of CLL. First, we found that elevated TAp63 expression levels are linked with adverse clinical outcomes, including disease relapse and shorter time-to-first treatment and overall survival. Next, prompted by the fact that TAp63 participates in an NF-κB/TAp63/BCL2 anti-apoptotic axis in activated mature normal B cells, we explored molecular links between TAp63 and BCL2 also in CLL. We documented a strong correlation at both the protein and the mRNA levels, alluding to the potential prosurvival role of TAp63. This claim was supported by inducible downregulation of TAp63 expression in the MEC1 CLL cell line using CRISPR, which resulted in downregulation of BCL2 expression. Next, using ChIP-sequencing, we examined whether BCL2 might constitute a transcriptional target of TAp63 and identified a significant binding profile of TAp63 in the BCL2 gene locus, across a genomic region previously characterized as a super-enhancer in CLL. Moreover, we identified high-confidence TAp63 binding regions in genes mainly implicated in immune response and DNA-damage procedures. Finally, we found that up-regulated TAp63 expression levels render CLL cells less responsive to apoptosis induction with the BCL2 inhibitor, venetoclax. On these grounds, TAp63 appears to act as a positive modulator of BCL2, hence contributing to the anti-apoptotic phenotype that underlies clinical aggressiveness and treatment resistance in CLL.

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“…SHM introduces high-frequency point mutations (10 -4 –10 -3 /base pair/cell division) in the variable regions of the Ig heavy and light chains higher than the rate of genome-wide spontaneous mutations (10–9), which facilitates iterative screening to obtain high-affinity antibodies ( 91 ). CSR events allow antibody-switching from IgM to IgG, IgA, or IgE isotypes by C-region exchange to achieve diverse effect functions.…”

Section: Hypoxic Regulation Of B Cell Biologymentioning

confidence: 99%

Hypoxia and hypoxia-inducible factor signals regulate the development, metabolism, and function of B cells

Zhang

et al. 2022

Front. Immunol.

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Hypoxia is a common hallmark of healthy tissues in physiological states or chronically inflamed tissues in pathological states. Mammalian cells sense and adapt to hypoxia mainly through hypoxia-inducible factor (HIF) signaling. Many studies have shown that hypoxia and HIF signaling play an important regulatory role in development and function of innate immune cells and T cells, but their role in B cell biology is still controversial. B cells experience a complex life cycle (including hematopoietic stem cells, pro-B cells, pre-B cells, immature B cells, mature naïve B cells, activated B cells, plasma cells, and memory B cells), and the partial pressure of oxygen (PO2) in the corresponding developmental niche of stage-specific B cells is highly dynamic, which suggests that hypoxia and HIF signaling may play an indispensable role in B cell biology. Based on the fact that hypoxia niches exist in the B cell life cycle, this review focuses on recent discoveries about how hypoxia and HIF signaling regulate the development, metabolism, and function of B cells, to facilitate a deep understanding of the role of hypoxia in B cell-mediated adaptive immunity and to provide novel strategies for vaccine adjuvant research and the treatment of immunity-related or infectious diseases.

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AID in Chronic Lymphocytic Leukemia: Induction and Action During Disease Progression

Cited by 17 publications

References 239 publications

Potent high-avidity neutralizing antibodies and T cell responses after COVID-19 vaccination in individuals with B cell lymphoma and multiple myeloma

Potent high-avidity neutralizing antibodies and T cell responses after COVID-19 vaccination in individuals with B cell lymphoma and multiple myeloma

The TΑp63/BCL2 axis represents a novel mechanism of clinical aggressiveness in chronic lymphocytic leukemia

Hypoxia and hypoxia-inducible factor signals regulate the development, metabolism, and function of B cells

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