ABSTRACT
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.
Subject(s)
Lymphoma, T-Cell, Peripheral , 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/geneticsABSTRACT
This work is aimed at assessing the presence of positive selection and/or shifts of the evolutionary rate in a fast-expanding HIV-1 subtype F1 transmission cluster affecting men who have sex with men in Spain. We applied Bayesian coalescent phylogenetics and selection analyses to 23 full-coding region sequences from patients belonging to that cluster, along with other 19â¯F1 epidemiologically-unrelated sequences. A shift in the overall evolutionary rate of the virus, explained by positively selected sites in the cluster, was detected. We also found one substitution in Nef (H89F) that was specific to the cluster and experienced positive selection. These results suggest that fast transmission could have been facilitated by some inherent genetic properties of this HIV-1 variant.
Subject(s)
Evolution, Molecular , Genome, Viral , Genomics , Genotype , HIV Infections/epidemiology , HIV Infections/virology , HIV-1/genetics , Antigens, Viral/immunology , Databases, Genetic , Epitopes, T-Lymphocyte/immunology , Genomics/methods , HIV Infections/immunology , HIV Infections/transmission , HIV-1/immunology , Humans , Phylogeny , Recombination, Genetic , Selection, Genetic , Sex Factors , Spain/epidemiologyABSTRACT
Nucleotide sequences of HIV isolates are obtained routinely to evaluate the presence of resistance mutations to antiretroviral drugs. But, beyond their clinical use, these and other viral sequences include a wealth of information that can be used to better understand and characterize the epidemiology of HIV in relevant populations. In this review, we provide a brief overview of the main methods used to analyze HIV sequences, the data bases where reference sequences can be obtained, and some caveats about the possible applications for public health of these analyses, along with some considerations about their limitations and correct usage to derive robust and reliable conclusions.