Biology and Molecular Pathogenesis of Mature T-Cell Lymphomas

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

“…Next, and given the proposed role for T cell receptor (TCR) signaling as an oncogenic driver in the pathogenesis of PTCL ( Cortes and Palomero, 2020 ; Warner et al, 2013 ), we analyzed the effect of Vav1-Myo1f expression on TCR signaling. Analysis of VAV1 phosphorylation showed a marked increase in VAV1 phospho-Tyr174 in Vav1-Myo1f -expressing CD4 + T cells compared with wild-type controls ( Figure 2A ).…”

“…This observation suggests that the transcriptional, signaling circuitries responsible for CD4 + T helper differentiation and plasticity could be of particular relevance in the pathogenesis of these diseases ( Timmins et al, 2020 ). Moreover, functional characterization of recurrent genomic alterations in PTCL has also demonstrated a driver role for PTCL-associated mutations in controlling T cell differentiation ( Cortes and Palomero, 2020 ).…”

“…Genomic studies have uncovered specific genetic drivers of PTCL-NOS. These include recurrent lesions in genes encoding epigenetic regulators ( TET2 , DNMT3A , IDH2 ), a highly prevalent RHOA G17V mutation characteristically associated with tumors bearing T-follicular helper (Tfh) characteristics, loss-of-function mutations in TP53 , and genetic alterations resulting in enhanced signaling downstream of T cell receptor activation ( Cortes and Palomero, 2020 ). Prominent among them are those resulting in increased VAV1 signaling ( Abate et al, 2017 ; Watatani et al, 2019 ).…”

The peripheral T-cell lymphoma: can we pivot from the chemotherapy-predicated paradigm?

“…Preclinical studies have demonstrated a causal relationship between mutations in TET2 and the development of both lymphoid and myeloid cancers [17] . Murine models with mutated TET2 demonstrated TFH cell proliferation and progression to PTCL with TFH phenotype after a prolonged latency, possibly due to dysregulation of both cytokine expression and T-cell differentiation [23,24] . Mutations in TET2 have been found in patients without malignancies, related to an entity named clonal hematopoiesis of indeterminate potential (CHIP), which highlights that aberrancies in TET2 are not enough for transformation but can predispose the cells to transform into diverse malignancies upon acquisition of secondary genetic hits.…”

Molecular Genetics in Epstein–Barr Virus-Associated Malignancies

“…The role of EBV infection in NKTCL has been hypothesized during the targeted killing of EBV-infected cells by NK/T cells. The patients with overlapping evidence of EBV- associated diseases are shown to have circulating EBV-infected NK/T cells (EBV positive NK/T cells) [ 46 , 47 ]. This positivity is due to the effect of the “trogocytosis” phenomenon caused by glycoproteins (gp 350, gp 42, and gp85) and cellular protein (CD 21).…”