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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1234-1245 |
| Number of pages | 12 |
| Journal | Blood |
| Volume | 128 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 1 2016 |
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ASJC Scopus subject areas
- Immunology
- Biochemistry
- Hematology
- Cell Biology
Cite this
Integrated mate-pair and RNA sequencing identifies novel, targetable gene fusions in peripheral T-cell lymphoma. / Luchtel, Rebecca; Razidlo, Gina; Dasari, Surendra; Zeng, Yu; Hu, Guangzhen; Knudson, Ryan A.; Greipp, Patricia T; Davila, Jaime I.; Johnson, Sarah H.; Porcher, Julie C.; Smadbeck, James; Eckloff, Bruce W.; Billadeau, Daniel D; Kurtin, Paul J.; Mc Niven, Mark A; Link, Brian K.; Ansell, Stephen Maxted; Cerhan, James R; Asmann, Yan; Vasmatzis, George; Feldman, Andrew L.
In: Blood, Vol. 128, No. 9, 01.09.2016, p. 1234-1245.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Integrated mate-pair and RNA sequencing identifies novel, targetable gene fusions in peripheral T-cell lymphoma
AU - Luchtel, Rebecca
AU - Razidlo, Gina
AU - Dasari, Surendra
AU - Zeng, Yu
AU - Hu, Guangzhen
AU - Knudson, Ryan A.
AU - Greipp, Patricia T
AU - Davila, Jaime I.
AU - Johnson, Sarah H.
AU - Porcher, Julie C.
AU - Smadbeck, James
AU - Eckloff, Bruce W.
AU - Billadeau, Daniel D
AU - Kurtin, Paul J.
AU - Mc Niven, Mark A
AU - Link, Brian K.
AU - Ansell, Stephen Maxted
AU - Cerhan, James R
AU - Asmann, Yan
AU - Vasmatzis, George
AU - Feldman, Andrew L
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84987622244&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84987622244&partnerID=8YFLogxK
U2 - 10.1182/blood-2016-03-707141
DO - 10.1182/blood-2016-03-707141
M3 - Article
C2 - 27297792
AN - SCOPUS:84987622244
VL - 128
SP - 1234
EP - 1245
JO - Blood
JF - Blood
SN - 0006-4971
IS - 9
ER -