Journal article
Integrated mate-pair and RNA sequencing identifies novel, targetable gene fusions in peripheral T-cell lymphoma
Blood, Vol.128(9), pp.1234-1245
09/01/2016
DOI: 10.1182/blood-2016-03-707141
PMCID: PMC5009513
PMID: 27297792
Abstract
Peripheral T-cell lymphomas (PTCLs) represent a heterogeneous group of T-cell malignancies that generally demonstrate aggressive clinical behavior, often are refractory to standard therapy, and remain significantly understudied. The most common World Health Organization subtype is PTCL, not otherwise specified (NOS), essentially a "wastebasket" category because of inadequate understanding to assign cases to a more specific diagnostic entity. Identification of novel fusion genes has contributed significantly to improving the classification, biologic understanding, and therapeutic targeting of PTCLs. Here, we integrated mate-pair DNA and RNA next-generation sequencing to identify chromosomal rearrangements encoding expressed fusion transcripts in PTCL, NOS. Two of 11 cases had novel fusions involving VAV1, encoding a truncated form of the VAV1 guanine nucleotide exchange factor important in T-cell receptor signaling. Fluorescence in situ hybridization studies identified VAV1 rearrangements in 10 of 148 PTCLs (7%). These were observed exclusively in PTCL, NOS (11%) and anaplastic large cell lymphoma (11%). In vitro, ectopic expression of a VAV1 fusion promoted cell growth and migration in a RAC1-dependent manner. This growth was inhibited by azathioprine, a clinically available RAC1 inhibitor. We also identified novel kinase gene fusions, ITK-FER and IKZF2-ERBB4, as candidate therapeutic targets that show similarities to known recurrent oncogenic ITK-SYK fusions and ERBB4 transcript variants in PTCLs, respectively. Additional novel and potentially clinically relevant fusions also were discovered. Together, these findings identify VAV1 fusions as recurrent and targetable events in PTCLs and highlight the potential for clinical sequencing to guide individualized therapy approaches for this group of aggressive malignancies.
Details
- Title: Subtitle
- Integrated mate-pair and RNA sequencing identifies novel, targetable gene fusions in peripheral T-cell lymphoma
- Creators
- Rebecca L Boddicker - Department of Laboratory Medicine and Pathology,Gina L Razidlo - National Clinical Research Center for Digestive DiseasesSurendra Dasari - §Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MNYu Zeng - Tongji UniversityGuangzhen Hu - Department of Laboratory Medicine and Pathology,Ryan A Knudson - Medical Genome Facility,Patricia T Greipp - Department of Laboratory Medicine and Pathology,Jaime I Davila - §Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MNSarah H Johnson - Department of Molecular Medicine, Mayo Clinic, Rochester, MN;Julie C Porcher - Department of Laboratory Medicine and Pathology,James B Smadbeck - Department of Laboratory Medicine and Pathology,Bruce W Eckloff - Medical Genome Facility,Daniel D Billadeau - Department of Biochemistry and Molecular Biology, andPaul J Kurtin - Department of Laboratory Medicine and Pathology,Mark A McNiven - National Clinical Research Center for Digestive DiseasesBrian K Link - University of IowaStephen M Ansell - Division of Hematology andJames R Cerhan - Mayo ClinicYan W Asmann - Mayo Clinic in FloridaGeorge Vasmatzis - Department of Molecular Medicine, Mayo Clinic, Rochester, MN;Andrew L Feldman - Department of Laboratory Medicine and Pathology,
- Resource Type
- Journal article
- Publication Details
- Blood, Vol.128(9), pp.1234-1245
- DOI
- 10.1182/blood-2016-03-707141
- PMID
- 27297792
- PMCID
- PMC5009513
- ISSN
- 0006-4971
- eISSN
- 1528-0020
- Grant note
- R01 CA104125 / NCI NIH HHS R01 CA177734 / NCI NIH HHS UL1 TR000135 / NCATS NIH HHS P30 CA015083 / NCI NIH HHS P50 CA097274 / NCI NIH HHS
- Language
- English
- Date published
- 09/01/2016
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Epidemiology; Internal Medicine
- Record Identifier
- 9984359591502771
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