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Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma

Diffuse large B cell lymphoma (DLBCL) is the most common hematologic malignancy and is characterized by a striking degree of heterogeneity. We enrolled a total of 1001 DLBCL patients and comprehensively defined the landscape of genetic mutations, copy number alterations and expression through whole-exome and transcriptome sequencing. We identified 150 genetic drivers of DLBCL including many novel, clinically relevant genes (e.g. SPEN, SETD1B and KLHL14). Genetic drivers were highly enriched among essential genes identified by CRISPR screening in DLBCL cell lines including those of immediate potential therapeutic relevance such as MTOR, SYK, SF3B1 and XPO1. RHOA emerged as a critical driver gene from our genetic analysis and CRISPR screen; we further delineated its functional role in vitro and in vivo models to define its role as an essential oncogene in DLBCL. Our work thus identifies the functional landscape of genetic drivers and their clinical and therapeutic relevance in DLBCL patients.

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Dataset ID Description Technology Samples
EGAD00001003600 Illumina HiSeq 2500 1776
Publications Citations
Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma.
Cell 171: 2017 481-494.e15
470
B cells with aberrant activation of Notch1 signaling promote Treg and Th2 cell-dominant T-cell responses via IL-33.
Blood Adv 2: 2018 2282-2295
14
Genome-wide discovery of somatic regulatory variants in diffuse large B-cell lymphoma.
Nat Commun 9: 2018 4001
71
Molecular High-Grade B-Cell Lymphoma: Defining a Poor-Risk Group That Requires Different Approaches to Therapy.
J Clin Oncol 37: 2019 202-212
94
The Identification and Interpretation of cis-Regulatory Noncoding Mutations in Cancer.
High Throughput 8: 2018 E1
3
Genome-defined African ancestry is associated with distinct mutations and worse survival in patients with diffuse large B-cell lymphoma.
Cancer 126: 2020 3493-3503
9
Optimized Doxorubicin Chemotherapy for Diffuse Large B-cell Lymphoma Exploits Nanocarrier Delivery to Transferrin Receptors.
Cancer Res 81: 2021 763-775
8
PRPS-ST: A protocol-agnostic self-training method for gene expression-based classification of blood cancers.
Blood Cancer Discov 1: 2020 244-257
2
An Autochthonous Mouse Model of Myd88- and BCL2-Driven Diffuse Large B-cell Lymphoma Reveals Actionable Molecular Vulnerabilities.
Blood Cancer Discov 2: 2021 70-91
18
The landscape of tumor cell states and ecosystems in diffuse large B cell lymphoma.
Cancer Cell 39: 2021 1422-1437.e10
59
Targeting mitochondrial respiration and the BCL2 family in high-grade MYC-associated B-cell lymphoma.
Mol Oncol 16: 2022 1132-1152
5
Clinical Impact of Immune Cells and Their Spatial Interactions in Diffuse Large B-Cell Lymphoma Microenvironment.
Clin Cancer Res 28: 2022 781-792
12
Disrupting the MYC-TFEB Circuit Impairs Amino Acid Homeostasis and Provokes Metabolic Anergy.
Cancer Res 82: 2022 1234-1250
5
PIM1 genetic alterations associated with distinct molecular profiles, phenotypes and drug responses in diffuse large B-cell lymphoma.
Clin Transl Med 12: 2022 e808
4
Tumoral microenvironment prevents de novo asparagine biosynthesis in B cell lymphoma, regardless of ASNS expression.
Sci Adv 8: 2022 eabn6491
3
TCR-Independent Metabolic Reprogramming Precedes Lymphoma-Driven Changes in T-cell Fate.
Cancer Immunol Res 10: 2022 1263-1279
0
Sex- and Female Age-Dependent Differences in Gene Expression in Diffuse Large B-Cell Lymphoma-Possible Estrogen Effects.
Cancers (Basel) 15: 2023 1298
1
Patterns of Oncogene Coexpression at Single-Cell Resolution Influence Survival in Lymphoma.
Cancer Discov 13: 2023 1144-1163
2