The whole-genome landscape of Burkitt lymphoma subtypes

Panea, Razvan; Love, Cassandra; Shingleton, Jennifer R.; Reddy, Anupama; Bailey, Jeffrey A.; Moormann, Ann M.; Otieno, Juliana A.; Ong’echa, John Michael; Oduor, Cliff I.; Schroeder, Kristin; Masalu, Nestory; Chao, Nelson J.; Agajanian, Megan; Major, Michael B.; Fedoriw, Yuri; Richards, Kristy L.; Rymkiewicz, Grzegorz; Miles, Rodney R.; Alobeid, Bachir; Bhagat, Govind; Flowers, Christopher R.; Ondrejka, Sarah L.; Hsi, Eric D.; Choi, William W.L.; Au-Yeung, Rex; Hartmann, Wolfgang; Lenz, Georg; Meyerson, Howard; Lin, Yen Yu; Zhuang, Yuan; Luftig, Micah A.; Waldrop, Alex; Dave, Tushar; Thakkar, Devang; Sahay, Harshit; Li, Guojie; Palus, Brooke C.; Seshadri, Vidya; Kim, So Young; Gascoyne, Randy D.; Levy, Shawn; Mukhopadyay, Minerva; Dunson, David B.; Davé, Sandeep S.

doi:10.1182/blood.2019001880

Cited by 121 publications

(117 citation statements)

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“…Of pathological relevance to BL, TCF4 encodes the helix-loop-helix transcription factor 4 reported to interact with ID3, which is inactivated by recurrent mutations in up to two-thirds of BL [6,7,15]. Somatic TCF4 deregulation has been implicated as an alternative mechanism of ID3-inactivating or TCF3activating mutations in BL [6,15]. Our somatic WES analysis showed that both patients lacked mutations in ID3 and TCF3.…”

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confidence: 93%

“…Of interest, the rs374301928-TCF4 locus appears to have been subject to early negative selection among vertebrate species and archaic hominins that may be indicative of relevant regulatory function [14]. Of pathological relevance to BL, TCF4 encodes the helix-loop-helix transcription factor 4 reported to interact with ID3, which is inactivated by recurrent mutations in up to two-thirds of BL [6,7,15]. Somatic TCF4 deregulation has been implicated as an alternative mechanism of ID3-inactivating or TCF3activating mutations in BL [6,15].…”

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confidence: 99%

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Endemic Burkitt Lymphoma in second-degree relatives in Northern Uganda: in-depth genome-wide analysis suggests clues about genetic susceptibility

et al. 2020

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Burkitt lymphoma (BL) is an aggressive B-cell lymphoma known to occur as endemic, sporadic, and immunodeficiency types [1]. Endemic Burkitt lymphoma (eBL) has been linked to Plasmodium falciparum malaria and Epstein-Barr virus infections [2, 3]. Regardless of type, BL is characterized by hallmark somatic IG-MYC chromosomal translocations [1], which cause BL in conjunction with other somatic genetic or epigenetic abnormalities, including in TP53, ID3, and TCF3 [4-7]. However, the role of germline genetic susceptibility in BL has not been well studied, although it has been suspected based on reports of familial BL clusters [8]. We report detailed genome-wide analyses in Northern Uganda, including whole-exome sequencing (WES) of eBL tumor and germline DNA (Fig. S1), and genome-wide genotyping array (for Methods see Supplementary data). Based on >4 million variants (Illumina 5 M array) in 198 eBL cases enrolled in the epidemiology of Burkitt lymphoma in East African children and minors (EMBLEM) case-control study (2010-2016) [2, 3], we incidentally

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confidence: 93%

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confidence: 99%

Endemic Burkitt Lymphoma in second-degree relatives in Northern Uganda: in-depth genome-wide analysis suggests clues about genetic susceptibility

et al. 2020

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“…[1][2][3] Genotypically, BL shows a translocation of MYC with the IG heavy or, less frequently, IG light chain genes, a simple karyotype, and a mutational spectrum distinct from that of other aggressive B-cell lymphomas, with common alterations of ID3, TCF3, CCND3, 4 and others. 5 BM infiltration is common, occurring in 30% of patients, so the BM is frequently the first site of biopsy. Some cases present with BM and peripheral blood (PB) involvement only, and these are referred to as Burkitt leukaemia.…”

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confidence: 99%

“…Alberto Zam o 1,2 Peter Johnston 3 Ayoma D Attygalle 4 Camille Laurent 5 Daniel A Arber 6 Falko Fend 7…”

Section: Acknowledgementsunclassified

Aggressive B‐cell lymphomas with a primary bone marrow presentation

et al. 2020

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Aggressive B‐cell lymphomas present as a heterogeneous spectrum of disease. A primary diagnosis in the bone marrow (BM) may be challenging in terms of diagnostic classification and clinical handling, owing to limited architectural information. Aggressive B‐cell lymphomas can be subdivided into entities that typically present primarily in the BM, and cases with BM involvement in which the bulk of disease is present in other organs. One main topic at the 2018 BM workshop of the European Association of Haematopathology/Society of Hematopathology was therefore aggressive B‐cell lymphomas with a primary BM presentation. The spectrum of cases submitted to this topic gave a good overview of commonly encountered problems, as well as unusual manifestations, and highlighted areas of imprecise disease definitions and diagnostic grey zones. The categories submitted to the workshop included cases of Burkitt lymphoma (BL) with unusual features, high‐grade B‐cell lymphomas (HG‐BCLs) with and without so‐called double/triple‐hit, and diffuse large B‐cell lymphomas (DLBCLs) with a primary BM presentation. Areas of difficulties included the morphological boundaries of HG‐BCL not otherwise specified, cases with MYC and bcl‐2 or bcl‐6 translocations and terminal deoxynucleotidyl transferase (TdT) expression, which were categorised as B‐cell lymphoblastic leukaemia/lymphoma if most cells showed TdT positivity, and the clinicopathological overlap between intravascular large B‐cell lymphoma, CD5‐positive DLBCL, and DLBCL with primary presentations in the BM, spleen, and liver. This review summarises our understanding of the main aggressive B‐cell lymphoma categories with a common primary BM presentation and potential problem areas, and makes suggestions for the immunophenotypic and genetic work‐up, illustrated by the interesting and challenging cases submitted to the workshop.

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“…Acute lymphoblastic leukemia (ALL) is the most common type of leukemia, and is characterized by uncontrolled proliferation of immature lymphoid cells [1,2]. Despite signi cant advances over the past few decades to develop treatments for ALL, ~25% of children and half of the adults do not respond to chemotherapy or relapse [3][4][5].…”

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confidence: 99%

Alantolactone inhibits cell autophagy and promotes apoptosis via AP2M1 in acute lymphoblastic leukemia

Shi

Lan

Wang

et al. 2020

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Background: Acute lymphoblastic leukemia (ALL) is an aggressive hematopoietic malignancy that is most commonly observed in children. Alantolactone (ALT) has been reported to exhibit anti-tumor activity in different types of cancer. The aim of the present study was to investigate the anti-tumor activity and molecular mechanism of ALT in ALL. Methods: ALL cell lines were treated with 1, 5 and 10 μM ALT, and cell viability was assessed using an MTT assay and RNA sequencing. Flow cytometry, JC-1 staining and immunofluorescence staining assays were used to measure cell apoptosis and autophagy. Additionally, western blot analysis was used to detect expression of apoptosis and autophagy related proteins. Finally, the effects of ALT on tumor growth were assessed in a BV173 xenograft nude mouse model. Results: ALT inhibited the proliferation of ALL cells in a dose-dependent manner. Additionally, it was demonstrated that ALT inhibited cell proliferation, colony formation, autophagy, induced apoptosis and reduced tumor growth in vivo through upregulating the expression of adaptor related protein complex 2 subunit mu 1 (AP2M1). Moreover, the autophagy activator rapamycin, attenuated the pro-apoptotic effects of ALT on BV173 and NALM6 cell lines. Overexpression of AP2M1 decreased the expression of Beclin1 and the LC3-II/LC3-1 ratio, and increased p62 expression. Knockdown of Beclin1 increased the levels of bax, cleaved caspase 3 and cytochrome C, and decreased bcl-2 expression. Conclusions: The present study demonstrated that ALT exerts anti-tumor activity through inducing apoptosis and inhibiting autophagy by upregulating AP2M1 in ALL, highlighting a potential therapeutic strategy for treatment of ALL.

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The whole-genome landscape of Burkitt lymphoma subtypes

Abstract: Key Points We investigated all 3 subtypes of BL by WGS and transcriptome sequencing. Experimental validation through CRISPR screening and mouse models provides a better functional understanding of BL genetic drivers.

Cited by 121 publications

References 30 publications

Endemic Burkitt Lymphoma in second-degree relatives in Northern Uganda: in-depth genome-wide analysis suggests clues about genetic susceptibility

Endemic Burkitt Lymphoma in second-degree relatives in Northern Uganda: in-depth genome-wide analysis suggests clues about genetic susceptibility

Aggressive B‐cell lymphomas with a primary bone marrow presentation

Alantolactone inhibits cell autophagy and promotes apoptosis via AP2M1 in acute lymphoblastic leukemia

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