Integrated mate-pair and RNA sequencing identifies novel, targetable gene fusions in peripheral T-cell lymphoma

Rebecca Luchtel, Gina Razidlo, Surendra Dasari, Yu Zeng, Guangzhen Hu, Ryan A. Knudson, Patricia T Greipp, Jaime I. Davila, Sarah H. Johnson, Julie C. Porcher, James Smadbeck, Bruce W. Eckloff, Daniel D Billadeau, Paul J. Kurtin, Mark A Mc Niven, Brian K. Link, Stephen Maxted Ansell, James R Cerhan, Yan Asmann, George VasmatzisAndrew L Feldman

Research output: Contribution to journalArticle

45 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)1234-1245
Number of pages12
JournalBlood
Volume128
Issue number9
DOIs
StatePublished - Sep 1 2016

Fingerprint

Peripheral T-Cell Lymphoma
RNA Sequence Analysis
T-cells
Gene Fusion
Fusion reactions
Genes
RNA
Anaplastic Large-Cell Lymphoma
Guanine Nucleotide Exchange Factors
Azathioprine
Group Psychotherapy
Growth
T-Cell Antigen Receptor
Fluorescence In Situ Hybridization
Cell growth
Cell Movement
Neoplasms
Refractory materials
Phosphotransferases
Therapeutics

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 journalArticle

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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.",
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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

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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.

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