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evidence to the clonal hematopoiesis story, mice with defects in both TET2 and RHOA developed myeloid
[35]
tumors before seven months but tended to produce T-cell lymphomas after this time . One possibility,
suggested by the experimental evidence described above, is that loss-of-function mutation in epigenetic
factors, e.g., TET2, is an early event in the process of transformation that requires a second and final hit in
RHOA G17V to induce cell differentiation toward TFH and the development of AITL.

VAV1 encodes a hematopoietic-specific Rho family-specific guanine exchange factor and is found to be
mutated in up to 10% of AITL and PTCL-NOS patients . These mutations generally include recurrent
[38]
frame deletion that is generated by alternative splicing and multiple VAV1 gene fusions. Mutations in
RHOA and VAV1 are mutually exclusive, suggesting that they could be affecting the same genetic
[39]
pathway .

Mutations in T-cell receptor pathway genes
Defects in TCR signaling can result in aberrant activation, differentiation, and proliferation of T-cells. AITL
or PTCL-NOS with a TFH phenotype specimens have recurrent mutations in T-cell receptor signaling
including phospho-lipase C gamma 1 (PLCG1), CD28, phosphoinositide-3-kinase (PI3K) regulatory and
[40]
catalytic subunits as well as other genes . Activating TCR alterations seemed to be adequate to drive
malignant transformation since these cases rarely had more than one TCR gene mutation. TCR
dysregulation was also associated with activation of NF-κB, leading to cellular proliferation. CD28
mutations were reported in both AITL and PTCL NOS subtypes and was found to bind its ligand more
[41]
tightly than wild-type CD28, which presumably is responsible for its activating ability . Interestingly,
CD28-mutated AITL patients have worse survival compared to wild-type cases . The most common
[41]
mutation in PLCG1 p.Ser345Phe interferes with the enzymatic catalytic domain to increase NF-κB/NFAT
activity and, interestingly, is also found in CTCL, suggesting a shared mechanism of disease .
[42]
Other insights into the genetic drivers of PTCL NOS
Consistent with the heterogeneous presentations of the PTCL, there is a variety of mutations reported to
describe the diversity. In addition to the molecular drivers of disease described above, chromosomal
translocations may offer insight into oncogenic pathways and potential therapeutic targets. The
translocation t(5;9)(q33;q22) between interleukin-2-inducible T-cell kinase (ITK) and spleen tyrosine kinase
(SYK) has been reported in 17% of PTCL NOS and 18% of PTCL NOS TFH patients [43,44] . By
immunohistochemistry, the majority (94%) of PTCL samples overexpress SYK . A mechanistic murine
[45]
model demonstrated that overexpression of an ITK-SYK fusion gene is sufficient to activate TCR signaling
and drive the production of T-cell lymphomas [44,46] . Other novel kinase fusion genes have been described
[38]
and warrant further investigation . Recent analysis of a large PTCL NOS cohort has identified additional
altered genes, such as YTHDF2 and PD1, and even more interestingly, a novel subtype characterized by
TP53 and/or CDKN2A mutations and deletions has been described and associated, not surprisingly, with a
worse prognosis .
[47]

In summary, the implementation of high-throughput genomic techniques in the field of PTCL has brought
significant improvement in our understanding of the molecular complexity and genetic drivers of the
disease. The identification of recurrently deregulated pathways has paved the way to the development of
more rationally planned drug development and to the design of early phase clinical trials aiming to target
these pathways that will hopefully yield better clinical outcomes for patients with PTCL.