Frequent mutations in the amino-terminal domain of BCL7A impair its tumor suppressor role in DLBCL

Baliñas-Gavira, Carlos; Rodríguez, María I.; Andrades, Álvaro; Cuadros, Marta; Álvarez-Pérez, Juan Carlos; Álvarez-Prado, Ángel F.; Yébenes, Virginia G. de; Sánchez‐Hernández, Sabina; Fernández-Vigo, Elvira; Muñoz, Javier; Martin, F. Elizabeth; Ramiro, Almudena R.; Martínez-Climent, José A.; Medina, Pedro

doi:10.1038/s41375-020-0919-5

Cited by 30 publications

(42 citation statements)

References 67 publications

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“…SWI/SNF chromatin remodeling complexes regulate the transcriptional accessibility of DNA by mobilizing histone octamers to adjacent DNA positions [ 102 , 103 ]. Point mutations of BCL7A , a subunit of SWI/SNF complexes, is enriched in the first splice donor and results in BCL7A inactivation, damaging BCL7A binding to SWI/SNF complex [ 19 , 21 , 22 , 104 ], while wild BCL7A exhibits a tumor-suppressing role [ 104 ]. ARID1A is another subunit of SWI/SNF chromatin remodeling complexes.…”

Section: Genetic Alterations In Dhlmentioning

confidence: 99%

Altered pathways and targeted therapy in double hit lymphoma

Zhuang

Che

et al. 2022

J Hematol Oncol

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High-grade B-cell lymphoma with translocations involving MYC and BCL2 or BCL6, usually referred to as double hit lymphoma (DHL), is an aggressive hematological malignance with distinct genetic features and poor clinical prognosis. Current standard chemoimmunotherapy fails to confer satisfying outcomes and few targeted therapeutics are available for the treatment against DHL. Recently, the delineating of the genetic landscape in tumors has provided insight into both biology and targeted therapies. Therefore, it is essential to understand the altered signaling pathways of DHL to develop treatment strategies with better clinical benefits. Herein, we summarized the genetic alterations in the two DHL subtypes (DHL-BCL2 and DHL-BCL6). We further elucidate their implications on cellular processes, including anti-apoptosis, epigenetic regulations, B-cell receptor signaling, and immune escape. Ongoing and potential therapeutic strategies and targeted drugs steered by these alterations were reviewed accordingly. Based on these findings, we also discuss the therapeutic vulnerabilities that coincide with these genetic changes. We believe that the understanding of the DHL studies will provide insight into this disease and capacitate the finding of more effective treatment strategies.

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Section: Genetic Alterations In Dhlmentioning

confidence: 99%

Altered pathways and targeted therapy in double hit lymphoma

Zhuang

Che

et al. 2022

J Hematol Oncol

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“…2c). BCL7A frequently undergoes biallelic inactivation in diffuse large B-Cell lymphoma, and our data identify a mechanistic consequence of its loss in this disease 46 . The results of our investigation into ARPs function align with previous work on a yeast remodeler showing that the ARP module enhances the efficiency with which ATP hydrolysis is coupled to DNA translocation 27 , highlighting the evolutionary conservation of regulatory logic within SWI/SNF family remodelers.…”

Section: Discussionmentioning

confidence: 56%

A system for CBAF reconstitution reveals roles for BAF47 domains and BCL7 in nucleosome ejection

Mulvihill

Nelson

Verma

et al. 2021

Preprint

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Canonical BAF (CBAF) is an essential 12-protein chromatin-remodeling complex that slides and/or ejects nucleosomes using the alternative catalytic ATP-dependent DNA translocases BRG1 or BRM. Currently, the regulation of BRG1/BRM activity and nucleosome ejection remain incompletely understood. To address this, we developed a system for full CBAF reconstitution and purification, and created a novel nucleosome ejection assay. ARID1A and DPF2 were dispensable for assembly and chromatin remodeling activity, contrasting with prior work. The actin-related protein BAF53A and β-actin components interacted and enhanced DNA translocation, and were required for BCL7A incorporation, which potentiated ejection. BAF47 also regulated ejection, utilizing two stimulatory domains and an autoinhibitory domain. Finally, we provide evidence for ‘direct’ nucleosome ejection at low nucleosome density on closed circular arrays. Taken together, we provide powerful new tools for CBAF mechanistic investigation and reveal new roles for several CBAF components.

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“…BCL7A encodes a subunit of the SWI/SNF complex and has been described as a tumor suppressor in B-cell non-Hodgkin lymphomas. 13,14 Cytokine inducible SH2 containing protein (CISH) is a member of the SOCS family which regulates cytokine receptor signaling through the JAK/STAT pathway. 15 B2M, BCL7A, GNA13, ITPKB, and SOCS1 tended to have more than one nonsynonymous mutation in the same patient (Figure 1c).…”

Section: Resultsmentioning

confidence: 99%

Molecular evolution of classic Hodgkin lymphoma revealed through whole genome sequencing of Hodgkin and Reed Sternberg cells

Maura

Ziccheddu

Xiang

et al. 2021

Preprint

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The rarity of malignant Hodgkin and Reed Sternberg (HRS) cells within a classic Hodgkin lymphoma (cHL) biopsy limits the ability to study the genomics of cHL. To circumvent this, our group has previously optimized fluorescence-activated cell sorting to purify HRS cells. Here we leveraged this method to report the first whole genome sequencing landscape of HRS cells and reconstruct the chronology and likely etiology of pathogenic events prior to the clinical diagnosis of cHL. We identified alterations in driver genes not previously described in cHL, a high activity of the APOBEC mutational signature, and the presence complex structural variants including chromothripsis. We found that the high ploidy observed in cHL is often acquired through multiple, independent large chromosomal gain events including whole genome duplication. The first of these likely occurs several years prior to the diagnosis of cHL, and the last gains typically occur very close to the time of diagnosis. Evolutionary timing analyses revealed that driver mutations in B2M, BCL7A, GNA13, and PTPN1, and the onset of AID driven mutagenesis usually preceded large chromosomal gains. The study provides the first temporal reconstruction of cHL pathogenesis and suggests a relatively long time course between the first pathogenic event and the clinical diagnosis.

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Frequent mutations in the amino-terminal domain of BCL7A impair its tumor suppressor role in DLBCL

Cited by 30 publications

References 67 publications

Altered pathways and targeted therapy in double hit lymphoma

Altered pathways and targeted therapy in double hit lymphoma

A system for CBAF reconstitution reveals roles for BAF47 domains and BCL7 in nucleosome ejection

Molecular evolution of classic Hodgkin lymphoma revealed through whole genome sequencing of Hodgkin and Reed Sternberg cells

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