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

Cell Rep. 2022 Apr 19;39(3):110695. doi: 10.1016/j.celrep.2022.110695.


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.

Keywords: CP: Cancer; GATA3; T cell differentiation; VAV1; VAV1-MYO1F; peripheral T cell lymphoma; tumor microenvironment; tumor-associated macrophages.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Fusion
  • Lymphoma, T-Cell, Peripheral* / genetics
  • Lymphoma, T-Cell, Peripheral* / metabolism
  • Lymphoma, T-Cell, Peripheral* / pathology
  • Macrophages / metabolism
  • Mice
  • Myosin Type I / genetics
  • Oncogenes
  • Proto-Oncogene Proteins c-vav / genetics
  • Proto-Oncogene Proteins c-vav / metabolism
  • Tumor Microenvironment / genetics


  • Myo1f protein, mouse
  • Proto-Oncogene Proteins c-vav
  • Vav1 protein, mouse
  • Myosin Type I