Oncogenic Vav1-Myo1f induces therapeutically targetable macrophage-rich tumor microenvironment in peripheral T cell lymphoma

Peripheral T cell lymphoma not otherwise specified (PTCL-NOS) comprises heterogeneous lymphoid malignancies characterized by pleomorphic lymphocytes and variable inflammatory cell-rich tumor microenvironment. Genetic drivers in PTCL-NOS include genomic alterations affecting the VAV1 oncogene; howeve...

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Authors: Rodriguez Cortes, Jose|||0000-0002-4457-3850; Filip, I.; Albero Gallego, Robert|||0000-0001-5527-0997; Patiño-Galindo, Juan Ángel|||0000-0002-6832-7179; Aidan Quinn, Stuart|||0000-0002-6557-9186; Lin, W.H.W.; Laurent, Anouchka|||0000-0001-7726-4723; Shih, Bobby|||0000-0003-0193-8263; Brown, Jessie A.|||0000-0003-2396-5393; Cooke, A.J.; Mackey, Adam|||0000-0003-0064-6373; Einson, Jonah|||0000-0002-5564-1003; Zairis, Sakellarios; Rivas-Delgado, Alfredo|||0000-0003-0385-3415; Laginestra, Maria Antonella|||0000-0003-2012-1283; Pileri, Stefano|||0000-0001-8032-5128; Campo, Elias|||0000-0001-9850-9793; Bhagat, Govind|||0000-0001-6250-048X; Ferrando, Adolfo A.|||0000-0002-6212-8574; Rabadan, Raul|||0000-0001-7946-9255; Palomero, Teresa|||0000-0001-9851-3207
Format: Article
Publication date:2022
Country:España
Institution:Universitat Autònoma de Barcelona
Repository:Dipòsit Digital de Documents de la UAB
Language:English
OAI Identifier:oai:ddd.uab.cat:321646
Online Access:https://ddd.uab.cat/record/321646
https://dx.doi.org/urn:doi:10.1016/j.celrep.2022.110695
Access Level:Open access
Summary:Peripheral T cell lymphoma not otherwise specified (PTCL-NOS) comprises heterogeneous lymphoid malignancies characterized by pleomorphic lymphocytes and variable inflammatory cell-rich tumor microenvironment. Genetic drivers in PTCL-NOS include genomic alterations affecting the VAV1 oncogene; however, their specific role and mechanisms in PTCL-NOS remain incompletely understood. Here we show that expression of Vav1-Myo1f, a recurrent PTCL-associated VAV1 fusion, induces oncogenic transformation of CD4 T cells. Notably, mouse Vav1-Myo1f lymphomas show T helper type 2 features analogous to high-risk GATA3 human PTCL. Single-cell transcriptome analysis reveals that Vav1-Myo1f alters T cell differentiation and leads to accumulation of tumor-associated macrophages (TAMs) in the tumor microenvironment, a feature linked with aggressiveness in human PTCL. Importantly, therapeutic targeting of TAMs induces strong anti-lymphoma effects, highlighting the lymphoma cells' dependency on the microenvironment. These results demonstrate an oncogenic role for Vav1-Myo1f in the pathogenesis of PTCL, involving deregulation in T cell polarization, and identify the lymphoma-associated macrophage-tumor microenvironment as a therapeutic target in PTCL.

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