Integrated mate-pair and RNA sequencing identifies novel, targetable gene fusions in peripheral T-cell lymphoma.
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.
Department of Laboratory Medicine and Pathology.
Rebecca L
RL
Boddicker
Center for Basic Research in Digestive Diseases, Division of Gastroenterology & Hepatology, Department of Biochemistry and Molecular Biology, and.
Gina L
GL
Razidlo
Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN;
Surendra
S
Dasari
Department of Laboratory Medicine and Pathology, Department of Pathology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China;
Yu
Y
Zeng
Department of Laboratory Medicine and Pathology.
Guangzhen
G
Hu
Medical Genome Facility.
Ryan A
RA
Knudson
Department of Laboratory Medicine and Pathology, Medical Genome Facility.
Patricia T
PT
Greipp
Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN;
Jaime I
JI
Davila
Center for Individualized Medicine, and Department of Molecular Medicine, Mayo Clinic, Rochester, MN;
Sarah H
SH
Johnson
Department of Laboratory Medicine and Pathology.
Julie C
JC
Porcher
Department of Laboratory Medicine and Pathology.
James B
JB
Smadbeck
Medical Genome Facility.
Bruce W
BW
Eckloff
Department of Biochemistry and Molecular Biology, and.
Daniel D
DD
Billadeau
Department of Laboratory Medicine and Pathology.
Paul J
PJ
Kurtin
Center for Basic Research in Digestive Diseases, Division of Gastroenterology & Hepatology, Department of Biochemistry and Molecular Biology, and.
Mark A
MA
McNiven
Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA;
Brian K
BK
Link
Division of Hematology and.
Stephen M
SM
Ansell
Department of Health Sciences Research, Mayo Clinic, Rochester, MN; and.
James R
JR
Cerhan
Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL.
Yan W
YW
Asmann
Center for Individualized Medicine, and Department of Molecular Medicine, Mayo Clinic, Rochester, MN;
George
G
Vasmatzis
Department of Laboratory Medicine and Pathology.
Andrew L
AL
Feldman
D000368:Aged; D000818:Animals; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D019169:Jurkat Cells; D016411:Lymphoma, T-Cell, Peripheral / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D041681:NIH 3T3 Cells; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism
D015514:Oncogene Proteins, Fusion