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1101 Expression of Vav1-Myo1F Fusion Affects T-Cell Differentiation and Induces T-Cell Lymphoma

Program: Oral and Poster Abstracts
Session: 621. Lymphoma—Genetic/Epigenetic Biology: Poster I
Hematology Disease Topics & Pathways:
Diseases, T-Cell Lymphoma, Lymphoid Malignancies
Saturday, December 5, 2020, 7:00 AM-3:30 PM

Jose Rodriguez Cortes, PhD1*, Robert Albero Gallego, PhD2*, Ioan Filip, PhD3*, Juan Angel Patino, PhD4*, Anisha Cooke5*, Wen-Hsuan Lin6*, Anouchka P Laurent7*, Bobby B Shih8*, Aidan Quinn2*, Raul Rabadan, PhD3,9*, Adolfo A. Ferrando, MD, PhD5,10,11 and Teresa Palomero, PhD12

1Institute For Cancer Genetics, New York, NY
2Columbia University, New York, NY
3Department of Systems Biology, Columbia University, New York, NY
4Department of Systems Biology, Columbia University, New York
5Institute for Cancer Genetics, Columbia University, New York, NY
6Department of Pathology and Cell Biology, Columbia University, New York, NY
7Institute For Cancer Genetics, Columbia University, New York, NY
8Columbia University Medical Center, New York, NY
9Department of Biomedical Informatics, Columbia University, New York
10Department of Pediatrics, Columbia University, New York, NY
11Department of Pathology & Cell Biology, Columbia University, New York
12Department of Pathology and Cell Biology, Inst. for Cancer Genetics Columbia University, New York, NY

Peripheral T-cell lymphomas (PTCL) are highly aggressive, malignant hematologic tumors that arise from clonal proliferation of mature T-cells. Among these, angioimmunoblastic T-cell lymphoma (AITL), and peripheral T cell lymphomas not otherwise specified (PTCL, NOS) account for >45% diagnoses, show limited response to intensified chemotherapy treatment and are associated with dismal survival.

Genomic studies from our group have uncovered recurrent mutations and novel cancer-associated gene fusions involving the guanine nucleotide exchange factor VAV1 in AITL and PTCL, NOS. Interestingly, mutation co-occurrence analysis in AITL and PTCL, NOS showed significant mutual exclusivity of VAV1 genomic alterations and the highly prevalent RHOA mutations (p-value 0.0142), supporting a common mechanism of action.

Gene fusions involving VAV1 are characterized by the substitution of their auto-inhibitory C-terminal SH3 domains by different domains from their fusion partners, leading to increased activation of VAV1-dependent signaling pathways. Among them, the VAV1-MYO1F fusion shows the strongest increase in VAV1 activity and activation of the mitogen-activated protein kinase (ERK1/2), c-Jun N-terminal kinase (JNK) and nuclear factor of activated T-cells (NFAT) pathways.

To study the role of VAV1-MYO1F, we engineered a conditional knockin mouse that expresses the Vav1-myo1f fusion in CD4+ T-cells. Expression of Vav1-myo1f in CD4 T cells induces cell activation and alterations in T-cell specification, associated with up-regulation of master transcription factors involved in helper T-cell cell differentiation. Moreover, Vav1-Myo1f increased CD4+ T-cell survival upon cytokine withdrawal and enhanced Vav1 phosphorylation and activation of the MAPK pathway, resulting in increased cell activation and proliferation both in vivo and in vitro in response to TCR engagement.

Notably, expression of Vav1-Myo1f fusion in CD4+ T-cells is sufficient to induce development of fatal malignant lymphomas with a latency of 6-14 months. Histological examination showed disrupted splenic architecture associated with clonal expansion of CD4+ cells indicative of T-cell lymphoma with PTCL, NOS phenotype. Similar results were obtained in a genetic model that combined the expression of Vav1-myo1f with the deletion of the Tet2 epigenetic regulator. In both genetic models, tumor cells specifically present a memory cell-associated immunophenotype (CD44+ CD62L-) and characteristic Th2-like features including increased expression of the transcription factors Gata3 and c-Maf and the IL4 and Il10 cytokines.

Overall, these results demonstrate a direct oncogenic role for Vav1-Myo1f in the pathogenesis of PTCL, associated with deregulation of T-cell specification and of signaling programs critical for the control of T-cell proliferation.

Disclosures: Palomero: Kura Onclology: Research Funding.

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