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Blood. 2017 Oct 19;130(16):1819-1831. doi: 10.1182/blood-2017-02-767335. Epub 2017 Aug 11.

Adult high-grade B-cell lymphoma with Burkitt lymphoma signature: genomic features and potential therapeutic targets.

Author information

1
Pathology and Microbiology and.
2
Division of Hematology and Oncology, University of Nebraska Medical Center, Omaha, NE.
3
Department of Pathology, City of Hope National Medical Center, Duarte, CA.
4
Center for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada.
5
Department of Pathology, University of Würzburg and Comprehensive Cancer Center Mainfranken, Würzburg, Germany.
6
Department of Clinical Pathology, Robert-Bosch-Krankenhaus, and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
7
Hematopathology Unit, Hospital Clinic, Barcelona, Spain.
8
Department of Pathology, University of Arizona, Tucson, AZ.
9
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD.
10
Oregon Health Sciences Center, Portland, OR.
11
Institute of Human Genetics, University Hospital of Ulm, Ulm, Germany.
12
Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, UT.
13
Institute of Genome Sciences and Department of Medicine, Duke University Medical Center, Durham, NC.
14
Department of Pathology, University of Toronto, Toronto, ON, Canada.
15
Metabolism Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD.
16
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE; and.
17
Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX.

Abstract

The adult high-grade B-cell lymphomas sharing molecular features with Burkitt lymphoma (BL) are highly aggressive lymphomas with poor clinical outcome. High-resolution structural and functional genomic analysis of adult Burkitt lymphoma (BL) and high-grade B-cell lymphoma with BL gene signature (adult-molecularly defined BL [mBL]) revealed the MYC-ARF-p53 axis as the primary deregulated pathway. Adult-mBL had either unique or more frequent genomic aberrations (del13q14, del17p, gain8q24, and gain18q21) compared with pediatric-mBL, but shared commonly mutated genes. Mutations in genes promoting the tonic B-cell receptor (BCR)→PI3K pathway (TCF3 and ID3) did not differ by age, whereas effectors of chronic BCR→NF-κB signaling were associated with adult-mBL. A subset of adult-mBL had BCL2 translocation and mutation and elevated BCL2 mRNA and protein expression, but had a mutation profile similar to mBL. These double-hit lymphomas may have arisen from a tumor precursor that acquired both BCL2 and MYC translocations and/or KMT2D (MLL2) mutation. Gain/amplification of MIR17HG and its paralogue loci was observed in 50% of adult-mBL. In vitro studies suggested miR-17∼92's role in constitutive activation of BCR signaling and sensitivity to ibrutinib. Overall integrative analysis identified an interrelated gene network affected by copy number and mutation, leading to disruption of the p53 pathway and the BCR→PI3K or NF-κB activation, which can be further exploited in vivo by small-molecule inhibitors for effective therapy in adult-mBL.

PMID:
28801451
PMCID:
PMC5649549
DOI:
10.1182/blood-2017-02-767335
[Indexed for MEDLINE]
Free PMC Article

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