Genetic alterations affecting GTPases and T-cell receptor signaling in peripheral T-cell lymphomas

Abstract

Peripheral T-cell lymphomas (PTCLs) are rare, heterogeneous tumors with poor response to standard therapy and few targeted treatments available. The identification of mutations in the T-cell receptor (TCR) signaling pathway that either directly or indirectly affect Ras- and Rho-family GTPases is an emerging theme across PTCL subtypes. This review summarizes the role of GTPases in TCR signaling and highlights the constellation of mutations in this pathway among PTCLs. In particular, focus is given to the functional impact of the mutations and opportunities for targeted therapy. These mutations include activating mutations and gene fusions involving the guanine nucleotide exchange factor, VAV1, as well as activating and dominant negative mutations in the GTPases KRAS and RHOA, respectively. In addition to mutations directly affecting the GTPase pathway, TCR signaling mutations indirectly affecting Ras- and Rho-family GTPases involving genes such as CD28, FYN, LCK, and PLCG1 are also reviewed.

Keywords: GTPase; RAC1; RHOA; T cell signaling; VAV1; fusion protein; mutation; peripheral T-cell lymphoma.

Figures

Figure 1.

(A) Activation cycle of small GTPases. Ras and Rho family GTPases are activated at the cell membrane by GEFs, which catalyze the release of GDP and promote the loading of GTP, thereby inducing binding to effector proteins. GTPase activating proteins (GAPs) facilitate the hydrolysis of GTP to GDP, thereby inactivating the GTPase. Membrane targeting of GTPases is also regulated by guanine nucleotide dissociation inhibitors (GDIs, not shown). (B) Role of GTPases in T-cell receptor (TCR) signaling. Activation of the TCR stimulates activation of Ras through multiple mechanisms, including PLCγ-mediated generation of DAG, which recruits the Ras guanosine nucleotide exchange factor (GEF) GRP and through recruitment of another Ras GEF, SOS. Rho family GTPases including RAC are activated by multiple GEFs, including VAV1, which is activated by tyrosine phosphorylation (as reviewed in references, 8, 10, 52 and others).

Figure 2.

Three-centimeter lymph node from a 55 year-old male with peripheral T-cell lymphoma, not otherwise specified, bearing a chromosomal rearrangement of the GEF gene VAV1. VAV1 rearrangements are seen recurrently in PTCL (see text).30 (A) Photomicrograph of the lymph node biopsy (hematoxylin and eosin stain; original magnification, 10×). The architecture of the lymph node parenchyma (p) has been effaced by the infiltrating lymphoma cells. c, lymph node capsule. (B) Fluorescence in situ hybridization (FISH) image of a single lymphoma cell nucleus (stained blue). The DNA has been hybridized with red and green fluorescent probes flanking the VAV1 locus. One VAV1 allele shows a normal red-green fusion signal (f), whereas the red and green signals of the other allele are split (s), indicating a VAV1 rearrangement.