Aging Predisposes B cells to Malignancy by Activating c-Myc and Perturbing the Genome and Epigenome

Abstract Age is the single major risk factor for human cancer, but naturally occurring cancers are rarely studied in aging models. Like humans, mice spontaneously develop cancer with age, and standard laboratory strains are predisposed for B-cell lymphoma. Here, we uncover how B-cell lymphoma develops as a consequence of the aging immune system. We found that aged B cells acquire somatic mutations in tumor suppressors and oncogenes (e.g. Trp53, Pim1, and Myh11) and undergo monoclonal expansions, with some clones representing 86% of splenic B cells. Clonal B cells had hypermethylated promoters and globally silenced expression, suggesting a role of DNA methylation in clonal selection of premalignant B cells. B-cell size, spleen weight, and a novel population of B cells, which we named Myc+ cells, emerged as convenient markers of malignancy. High-throughput analyses of clonal B cells and the use of genetic mouse models revealed that c-Myc drives B-cell size increase and clonal expansion with age. Phoshoproteome and co-culture experiments revealed that c-Myc is activated by signals from the aging microenvironment. Moreover, single-cell RNA-seq suggested that clonal B cells originate from age-associated B cells, further underlying the importance of aging environment in cancer transformation. Longitudinal analyses demonstrated a negative impact of premalignant B cells on mouse lifespan and linked it to age-related myeloid bias. Together, our study revealed cell-autonomous changes that cooperate with the aging microenvironment to give rise to preneoplastic B cells. This stidy established a novel model to study how aging predisposes cells to cancer transformation.

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Aging predisposes B cells to malignancy by activating c-Myc and perturbing the genome and epigenome

10.1101/2021.02.23.432500 ◽

2021 ◽

Author(s):

Anastasia V. Shindyapina ◽

José P. Castro ◽

Alessandro Barbieri ◽

Olga S. Strelkova ◽

João A. Paulo ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Cell Lymphoma ◽

Human Cancer ◽

Laboratory Mouse ◽

B Cell Lymphoma ◽

Mouse Strains ◽

Human B Cells ◽

Early Markers ◽

Established Cell

AbstractAge is the single major risk factor for human cancer; however, naturally occurring cancers are rarely studied in aged animal models. Laboratory mouse strains spontaneously develop cancer with age and some predominantly die from B-cell lymphoma. Here, we uncover how B-cell lymphoma develops as a consequence of the aging immune system. We found that aged B cells undergo clonal expansions driven by genetic and epigenetic changes and established cell and spleen size as early markers of malignant transformation. High-throughput and omics assays of aged B cells and the use of mouse models revealed that c-Myc is a master regulator of B cell size and clonal expansion. A single-cell RNA-seq analysis suggested that clonal B cells originate from age-associated B cells, memory B cells that accumulate during aging. Further studies showed that c-Myc becomes activated in B cells in response to the aging microenvironment. Thus, c-Myc, aging environment, somatic mutations and the epigenome cooperate to give rise to clonal age-accelerated B cells, which we named Myc+ cells. We further show the relevance of this model to aged human B cells in blood and spleen. This study characterized a first mouse model that captures a natural transition of B cells to a prevalent type of cancer during aging.

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Long-Term Survival and Gradual Recovery of B Cells in Patients (Pts) with Refractory Large B Cell Lymphoma (LBCL) Treated with Axicabtagene Ciloleucel (Axi-Cel)

Transplantation and Cellular Therapy ◽

10.1016/s2666-6367(21)00520-0 ◽

2021 ◽

Vol 27 (3) ◽

pp. S404-S405

Author(s):

Caron A. Jacobson ◽

Frederick L. Locke ◽

Armin Ghobadi ◽

David B. Miklos ◽

Lazaros J. Lekakis ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Term Survival ◽

Long Term Survival ◽

Large B Cell Lymphoma ◽

Large B Cell

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B cells gone rogue: the intersection of diffuse large B cell lymphoma and autoimmune disease

Expert Review of Hematology ◽

10.1080/17474086.2016.1180972 ◽

2016 ◽

Vol 9 (6) ◽

pp. 553-561 ◽

Cited By ~ 4

Author(s):

Jean L. Koff ◽

Christopher R. Flowers

Keyword(s):

B Cells ◽

Autoimmune Disease ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell

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Primary Type3 (Non-ABC, Non-GCB) Subtype of Extranodal Diffuse Large B-Cell Lymphoma of the Thyroid Bearing No MYD88 Mutation by Padlock Probe Hybridization

Case Reports in Oncology ◽

10.1159/000477489 ◽

2017 ◽

Vol 10 (2) ◽

pp. 508-514 ◽

Cited By ~ 1

Author(s):

Yukiko Nishi ◽

Riko Kitazawa ◽

Ryuma Haraguchi ◽

Ayaka Ouchi ◽

Yasuo Ueda ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Malignant Lymphoma ◽

Cell Lymphoma ◽

Clinical Phenotype ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Japanese Female ◽

Old Japanese ◽

Large B Cell

Primary extranodal malignant lymphoma of the thyroid is a rare entity composed of mostly neoplastic transformation of germinal center-like B cells (GCB) or memory B cells. Other B-cell-type malignancies arising primarily in the thyroid have rarely been described. Immunohistochemical examination of autopsied primary malignant lymphoma of the thyroid in an 83-year-old Japanese female revealed the presence of a non-GCB subtype of diffuse large B-cell lymphoma (DLBCL) without the typical codon 206 or 265 missense mutation of MYD88. The lack of the highly oncogenic MYD88 gene mutation, frequently observed in DLBCL of the activated B-cell (ABC) subtype, and the detection of an extremely aggressive yet local clinical phenotype demonstrated that the present case was an exceptional entity of the type3 (non-GCB and non-ABC) subtype.

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Inactivating SOCS1 mutations are caused by aberrant somatic hypermutation and restricted to a subset of B-cell lymphoma entities

Blood ◽

10.1182/blood-2009-06-225839 ◽

2009 ◽

Vol 114 (20) ◽

pp. 4503-4506 ◽

Cited By ~ 81

Author(s):

Anja Mottok ◽

Christoph Renné ◽

Marc Seifert ◽

Elsie Oppermann ◽

Wolf Bechstein ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Cell Lymphoma ◽

Somatic Hypermutation ◽

B Cell Lymphoma ◽

Rare Mutations ◽

Large B Cell Lymphoma ◽

Mantle Cell ◽

Follicular Lymphomas ◽

Large B Cell

Abstract STATs are constitutively activated in several malignancies. In primary mediastinal large B-cell lymphoma and Hodgkin lymphoma (HL), inactivating mutations in SOCS1, an inhibitor of JAK/STAT signaling, contribute to deregulated STAT activity. Based on indications that the SOCS1 mutations are caused by the B cell–specific somatic hypermutation (SHM) process, we analyzed B-cell non-HL and normal B cells for mutations in SOCS1. One-fourth of diffuse large B-cell lymphoma and follicular lymphomas carried SOCS1 mutations, which were preferentially targeted to SHM hotspot motifs and frequently obviously inactivating. Rare mutations were observed in Burkitt lymphoma, plasmacytoma, and mantle cell lymphoma but not in tumors of a non–B-cell origin. Mutations in single-sorted germinal center B cells were infrequent relative to other genes mutated as byproducts of normal SHM, indicating that SOCS1 inactivation in primary mediastinal large B-cell lymphoma, HL, diffuse large B-cell lymphoma, and follicular lymphoma is frequently the result of aberrant SHM.

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BCL2 protein expression parallels its mRNA level in normal and malignant B cells

Blood ◽

10.1182/blood-2004-01-0243 ◽

2004 ◽

Vol 104 (9) ◽

pp. 2936-2939 ◽

Cited By ~ 17

Author(s):

Yulei Shen ◽

Javeed Iqbal ◽

James Z. Huang ◽

Guimei Zhou ◽

Wing C. Chan

Keyword(s):

B Cells ◽

Protein Expression ◽

B Cell ◽

Posttranscriptional Regulation ◽

Cell Lymphoma ◽

Dominant Role ◽

Mrna Level ◽

B Cell Lymphoma ◽

Transcriptional Level ◽

Bcl2 Protein

Abstract The regulation of B-cell lymphoma 2 (BCL2) protein expression in germinal center (GC) B cells has been controversial. Previous reports have indicated posttranscriptional regulation plays a dominant role. However, a number of recent studies contradicted these reports. Using real-time polymerase chain reaction (PCR) and Standardized Reverse Transcriptase-PCR (StaRT-PCR), we measured the level of mRNA expression in GC, mantle zone (MNZ), and marginal zone (MGZ) cells from laser capture microdissection. Both quantitative RT-PCR measurements of microdissected GC cells from tonsils showed that GC cells had low expression of BCL2 transcripts commensurate with the low protein expression level. These results are in agreement with microarray studies on fluorescence-activated cell sorter (FACS)-sorted cells and microdissected GC cells. We also examined BCL2 mRNA and protein expression on a series of 30 cases of diffuse large B-cell lymphoma (DLBCL) and found, in general, a good correlation. The results suggested that BCL2 protein expression is regulated at the transcriptional level in normal B cells and in the neoplastic cells in most B-cell lymphoproliferative disorders.

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Distinct roles for PARP-1 and PARP-2 in c-Myc-driven B-cell lymphoma in mice

Blood ◽

10.1182/blood.2021012805 ◽

2021 ◽

Author(s):

Miguel A Galindo-Campos ◽

Nura Lutfi ◽

Sarah Bonnin ◽

Carlos Martínez ◽

Talia Velasco-Hernandez ◽

...

Keyword(s):

Dna Damage ◽

B Cells ◽

B Cell ◽

Immune Escape ◽

Cell Lymphoma ◽

Tumour Progression ◽

Cancer Therapeutics ◽

B Cell Lymphoma ◽

B Cell Lymphomas ◽

Parp 1

Dysregulation of the c-Myc oncogene occurs in a wide variety of haematologic malignancies and its overexpression has been linked with aggressive tumour progression. Here, we show that Poly (ADP-ribose) polymerase (PARP)-1 and PARP-2 exert opposing influences on progression of c-Myc-driven B-cell lymphomas. PARP-1 and PARP-2 catalyse the synthesis and transfer of ADP-ribose units onto amino acid residues of acceptor proteins in response to DNA-strand breaks, playing a central role in the response to DNA damage. Accordingly, PARP inhibitors have emerged as promising new cancer therapeutics. However, the inhibitors currently available for clinical use are not able to discriminate between individual PARP proteins. We found that genetic deletion of PARP-2 prevents c-Myc-driven B-cell lymphomas, while PARP-1-deficiency accelerates lymphomagenesis in the Em-Myc mouse model of aggressive B-cell lymphoma. Loss of PARP-2 aggravates replication stress in pre-leukemic Em-Myc B cells resulting in accumulation of DNA damage and concomitant cell death that restricts the c-Myc-driven expansion of B cells, thereby providing protection against B-cell lymphoma. In contrast, PARP-1-deficiency induces a proinflammatory response, and an increase in regulatory T cells likely contributing to immune escape of B-cell lymphomas, resulting in an acceleration of lymphomagenesis. These findings pinpoint specific functions for PARP-1 and PARP-2 in c-Myc-driven lymphomagenesis with antagonistic consequences that may help inform the design of new PARP-centred therapeutic strategies with selective PARP-2 inhibition potentially representing a new therapeutic approach for the treatment of c-Myc-driven tumours.

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Antigenic modulation limits the efficacy of anti-CD20 antibodies: implications for antibody selection

Blood ◽

10.1182/blood-2010-01-263533 ◽

2010 ◽

Vol 115 (25) ◽

pp. 5191-5201 ◽

Cited By ~ 209

Author(s):

Stephen A. Beers ◽

Ruth R. French ◽

H. T. Claude Chan ◽

Sean H. Lim ◽

Timothy C. Jarrett ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Type I ◽

Type Ii ◽

Antigenic Modulation ◽

Lymphatic Leukemia ◽

Human B Cells ◽

Anti Cd20

Abstract Rituximab, a monoclonal antibody that targets CD20 on B cells, is now central to the treatment of a variety of malignant and autoimmune disorders. Despite this success, a substantial proportion of B-cell lymphomas are unresponsive or develop resistance, hence more potent anti-CD20 monoclonal antibodies (mAbs) are continuously being sought. Here we demonstrate that type II (tositumomab-like) anti-CD20 mAbs are 5 times more potent than type I (rituximab-like) reagents in depleting human CD20 Tg B cells, despite both operating exclusively via activatory Fcγ receptor–expressing macrophages. Much of this disparity in performance is attributable to type I mAb-mediated internalization of CD20 by B cells, leading to reduced macrophage recruitment and the degradation of CD20/mAb complexes, shortening mAb half-life. Importantly, human B cells from healthy donors and most cases of chronic lymphatic leukemia and mantle cell lymphoma, showed rapid CD20 internalization that paralleled that seen in the Tg mouse B cells, whereas most follicular lymphoma and diffuse large B-cell lymphoma cells were far more resistant to CD20 loss. We postulate that differences in CD20 modulation may play a central role in determining the relative efficacy of rituximab in treating these diseases and strengthen the case for focusing on type II anti-CD20 mAb in the clinic.

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Should Adolescents with NHL Be Treated as Old Children or Young Adults?

Hematology ◽

10.1182/asheducation-2007.1.297 ◽

2007 ◽

Vol 2007 (1) ◽

pp. 297-303 ◽

Cited By ~ 19

Author(s):

John T. Sandlund

Keyword(s):

Young Adults ◽

B Cell ◽

Burkitt Lymphoma ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Lymphoblastic Lymphoma ◽

Adolescents And Young Adults ◽

Large B Cell Lymphoma ◽

Age Related ◽

Large B Cell

Abstract The SEER (Surveillance, Epidemiology, and End Results) data for the years 1975–1998 show that children with non-Hodgkin lymphoma (NHL) have a better treatment outcome than do adults. Many factors may contribute to this age-related difference. Some factors are related to the patient (e.g., drug distribution and clearance, performance status, compliance, sex) whereas others pertain to tumor histology and biology. The spectrum of NHL subtypes is well known to differ in children and adults. From ages 5 through 14 years, Burkitt lymphoma is the predominant histologic subtype, whereas diffuse large B-cell lymphoma is most common in the 15- to 29-year age range. Because different treatment strategies are often used in children and adults with NHL, the choice of therapy for adolescents and young adults (ages 15 through 29 years) is challenging and somewhat controversial. It is reasonable to consider pediatric strategies for some adolescents and very young adults with NHL, and pediatric strategies are currently used to treat adults with certain subtypes of NHL (Burkitt lymphoma, lymphoblastic lymphoma). However, the use of pediatric strategies in adults does not guarantee a comparable outcome, as illustrated by trials for adult lymphoblastic lymphoma. There is clearly a need for further biologic study of NHL in children, adolescents, and young adults. Age-related differences in tumor biology have been demonstrated in anaplastic large-cell lymphoma (ALCL) and diffuse large B-cell lymphoma (DLBCL). Additional biologic data will not only improve prognosis and treatment stratification but, more important, will lead to the identification of specific molecular targets for therapy.

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