Activation-induced cytidine deaminase overexpression in double-hit lymphoma: potential target for novel anticancer therapy

Zhang, Jingcheng; Shi, Yifen; Zhao, Mingzhe; Hu, Huixian; Huang, He

doi:10.1038/s41598-020-71058-y

Cited by 6 publications

(7 citation statements)

References 44 publications

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“…This is further combined with the identification of novel putative mutational drivers (e.g., NCOR1, DTX1, LTB and STAT3) alongside several previously established mutational hotspots in HGBL-DH/TH. Of note, and in keeping with previous observations by Zhang et al, who described an increased AID activity in double-hit lymphomas, we observe a significant accumulation of mutations in known AID and SHMtargets such as PIM1, SOCS1 and others (49)(50)(51). Moreover, among these significantly mutated genes we describe ARID1A which emerges as a potential prognosticator of treatment response and outcome from our correlative assessment of clinical and molecular features of our present cohort, which was found to be independent from previously established clinical prognostic factors.…”

Section: Supporting This Assumption Pedrosa Et Al Have Shown Dlbcl With Bcl2 and Bcl6 Butsupporting

confidence: 92%

Mutational landscape of high-grade B-cell lymphoma with MYC-, BCL2 and/or BCL6 rearrangements characterized by whole-exome sequencing

et al. 2021

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High-grade B-cell lymphoma accompanied with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) poses a cytogenetically-defined provisional entity among aggressive B-cell lymphomas that is traditionally associated with unfavorable prognosis. To better understand the mutational and molecular landscape of HGBL-DH/TH we here performed whole-exome-sequencing and deep panel next-generation-sequencing (NGS) of 47 clinically annotated cases. Oncogenic drivers, mutational signatures and perturbed pathways were compared with data from follicular lymphoma (FL), diffuse large-B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL). We find an accumulation of oncogenic mutations in NOTCH, IL6/JAK/STAT and NFκB signaling pathways and delineate the mutational relationship within the continuum between FL/DLBCL, HGBL-DH/TH and BL. Further, we provide evidence of a molecular divergence between BCL2 and BCL6 rearranged HGBL-DH. Beyond a significant congruency with the C3/EZB DLBCL cluster in BCL2 rearranged cases on an exome-wide level, we observe an enrichment of the SBS6 mutation signature in BCL6 rearranged cases. Differential gene set enrichment and subsequent network propagation analysis according to cytogenetically defined subgroups revealed an impairment of TP53 and MYC pathway signaling in BCL2 rearranged cases, whereas BCL6 rearranged cases lacked this enrichment, but instead showed impairment of E2F targets. Intriguingly, HGBL-TH displayed intermediate mutational features in all three aspects. This study elucidates a recurrent pattern of mutational events driving FL into MYC-driven BCL2 rearranged HGBL, unveiling the mutational pathogenesis of this provisional entity. Through this refinement of the molecular taxonomy for aggressive, germinal-center derived B-cell lymphomas, this calls into question the current WHO-classification system, especially regarding the status of MYC/BCL6 rearranged HGBL.

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Section: Supporting This Assumption Pedrosa Et Al Have Shown Dlbcl With Bcl2 and Bcl6 Butsupporting

confidence: 92%

Mutational landscape of high-grade B-cell lymphoma with MYC-, BCL2 and/or BCL6 rearrangements characterized by whole-exome sequencing

et al. 2021

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“…The physiological function of AICDA is to promote the somatic hypermutation and class-switch recombination (CSR) of the immunoglobulin (Ig) loci. Aberrant expression of AICDA and its involvement in lymphomagenesis have been observed in different subtypes of B-cell lymphomas [ 36 , 37 ]. Our recent results demonstrate that HIV-1 Tat can induce aberrant expression of AICDA in peripheral blood B cells from HIV-infected individuals [ 38 ].…”

Section: Introductionmentioning

confidence: 99%

HIV-1 Tat Activates Akt/mTORC1 Pathway and AICDA Expression by Downregulating Its Transcriptional Inhibitors in B Cells

Akbay

Germini

Bissenbaev

et al. 2021

IJMS

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HIV-1 infects T cells, but the most frequent AIDS-related lymphomas are of B-cell origin. Molecular mechanisms of HIV-1-induced oncogenic transformation of B cells remain largely unknown. HIV-1 Tat protein may participate in this process by penetrating and regulating gene expression in B cells. Both immune and cancer cells can reprogram communications between extracellular signals and intracellular signaling pathways via the Akt/mTORC1 pathway, which plays a key role in the cellular response to various stimuli including viral infection. Here, we investigated the role of HIV-1 Tat on the modulation of the Akt/mTORC1 pathway in B cells. We found that HIV-1 Tat activated the Akt/mTORC1 signaling pathway; this leads to aberrant activation of activation-induced cytidine deaminase (AICDA) due to inhibition of the AICDA transcriptional repressors c-Myb and E2F8. These perturbations may ultimately lead to an increased genomic instability and proliferation that might cause B cell malignancies.

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“…As discussed, AID has a mutagenic activity that is related to oncogenesis. As noted in a study of double-hit lymphoma [ 34 ], targeting AID might be a good treatment regimen for IgG4+ MZL for which standard treatments have not yet been established [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Upregulated Expression of Activation-Induced Cytidine Deaminase in Ocular Adnexal Marginal Zone Lymphoma with IgG4-Positive Cells

Nishikori

Nishimura

Shibata

et al. 2021

IJMS

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Immunoglobulin G4-related disease (IgG4-RD) is a systemic disorder characterized by tissue fibrosis and intense lymphoplasmacytic infiltration, causing progressive organ dysfunction. Activation-induced cytidine deaminase (AID), a deaminase normally expressed in activated B-cells in germinal centers, edits ribonucleotides to induce somatic hypermutation and class switching of immunoglobulin. While AID expression is strictly controlled under physiological conditions, chronic inflammation has been noted to induce its upregulation to propel oncogenesis. We examined AID expression in IgG4-related ophthalmic disease (IgG4-ROD; n = 16), marginal zone lymphoma with IgG4-positive cells (IgG4+ MZL; n = 11), and marginal zone lymphoma without IgG4-positive cells (IgG4- MZL; n = 12) of ocular adnexa using immunohistochemical staining. Immunohistochemistry revealed significantly higher AID-intensity index in IgG4-ROD and IgG4+ MZL than IgG4- MZL (p < 0.001 and = 0.001, respectively). The present results suggest that IgG4-RD has several specific causes of AID up-regulation in addition to inflammation, and AID may be a driver of oncogenesis in IgG4-ROD to IgG4+ MZL.

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Activation-induced cytidine deaminase overexpression in double-hit lymphoma: potential target for novel anticancer therapy

Cited by 6 publications

References 44 publications

Mutational landscape of high-grade B-cell lymphoma with <i>MYC-</i>, <i>BCL2</i> and/or <i>BCL6</i> rearrangements characterized by whole-exome sequencing

Mutational landscape of high-grade B-cell lymphoma with <i>MYC-</i>, <i>BCL2</i> and/or <i>BCL6</i> rearrangements characterized by whole-exome sequencing

HIV-1 Tat Activates Akt/mTORC1 Pathway and AICDA Expression by Downregulating Its Transcriptional Inhibitors in B Cells

Upregulated Expression of Activation-Induced Cytidine Deaminase in Ocular Adnexal Marginal Zone Lymphoma with IgG4-Positive Cells

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