Mutations Affecting Genes in the Proximal T-Cell Receptor Signaling Pathway in Peripheral T-Cell Lymphoma

Abstract

Peripheral T-cell lymphoma (PTCL) comprises a heterogeneous group of mature T-cell malignancies. Recurrent activating mutations and fusions in genes related to the proximal TCR signaling pathway have been identified in preclinical and clinical studies. This review summarizes the genetic alterations affecting proximal TCR signaling identified from different subgroups of PTCL and the functional impact on TCR signaling and downstream pathways. These genetic abnormalities include mostly missense mutations, occasional indels, and gene fusions involving CD28, CARD11, the GTPase RHOA, the guanine nucleotide exchange factor VAV1, and kinases including FYN, ITK, PLCG1, PKCB, and PI3K subunits. Most of these aberrations are activating mutations that can potentially be targeted by inhibitors, some of which are being tested in clinical trials that are briefly outlined in this review. Finally, we focus on the molecular pathology of recently identified subgroups of PTCL-NOS and highlight the unique genetic profiles associated with PTCL-GATA3.

Unraveling the Oncogenic Potential of VAV1 in Human Cancer: Lessons from Mouse Models

“…The first reports about rearrangements/mutations in VAV1 in hematologic malignancies appeared in the last decade. VAV1 gene alterations, including translocations and missense/deletion mutations, account for 18% of adult T-cell leukemia/lymphoma (ATLL), 11% of anaplastic large cell lymphoma (ALCL), 7% to 11% of peripheral T-cell lymphomas not otherwise specified (PTCL-NOS), and 5% in angioimmunoblastic T-cell lymphoma (AITL) (reviewed in [95]). The various molecular lesions in these malignancies are detailed below.…”

The RHOA Mutation G17V Does Not Lead to Increased Migration of Human Malignant T Cells but Is Associated with Matrix Remodelling

“…In contrast with TET2 , DNMT3A , and IDH2 mutations, RHOA -G17V has only been observed in mature T cells; therefore, it is considered to be a late-stage mutation. RHOA encodes a small GTPase protein, which is a member of the RAS family and functions as a molecular regulator of diverse cellular functions, including downstream signalling of T-cell receptors [ 15 ] and cell motility. The most well characterized effector molecules of RHOA are the kinases RHO-associated coiled-coil-forming kinase (ROCK) I and II, PRK1, PKN, and Citron, which is involved in actomyosin contraction and actin polymerization, among other functions [ 16 , 17 ].…”

Peripheral T-Cell Lymphoma: From Biological Research to New Therapies

“…Regarding the clonal evolution of PTCL, genomic mutations commonly appear in molecules involved in the TCR signaling pathway, which Liu et al [ 3 ] focused on and comprehensively summarized in this special issue. Mutations in RHOA and vav guanine nucleotide exchange factor 1 (VAV1) are frequently observed in AITL, PTCL not otherwise specified (PTCL-NOS), and ATL.…”

“…Interestingly, genetic changes in TCR signaling and its costimulatory factors occur in almost all PTCL cases. As pointed out by Liu et al [ 3 ], PTCL is a cancer that is difficult to classify and diagnose and advancing a broader genomic analysis of PTCL would be useful for the classification of disease types based on mutations in TCR signaling components and for the development of new therapeutic agents.…”