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

Cell reports 2022 Apr 19

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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. Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Jose R Cortes, Ioan Filip, Robert Albero, Juan A Patiño-Galindo, S Aidan Quinn, Wen-Hsuan W Lin, Anouchka P Laurent, Bobby B Shih, Jessie A Brown, Anisha J Cooke, Adam Mackey, Jonah Einson, Sakellarios Zairis, Alfredo Rivas-Delgado, Maria Antonella Laginestra, Stefano Pileri, Elias Campo, Govind Bhagat, Adolfo A Ferrando, Raul Rabadan, Teresa Palomero. Oncogenic Vav1-Myo1f induces therapeutically targetable macrophage-rich tumor microenvironment in peripheral T cell lymphoma. Cell reports. 2022 Apr 19;39(3):110695