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Ma et al. J Cancer Metastasis Treat 2022;8:25 https://dx.doi.org/10.20517/2394-4722.2022.17 Page 3 of 20

Mutations in tet methylcytosine dioxygenase 2 (TET2), which encodes a methylcytosine dioxygenase that is
important in normal cell function, are commonly reported in myeloid diseases but are also seen in
[17]
lymphoid malignancies: 2% of B-cell lymphomas and almost 12% of PTCL including 33% of AITL . TET2
mutations with and without DNA methyltransferase 3 alpha (DNMT3A) mutations can be found in non-
tumor DNA in some PTCL patients, signifying that clonal hematopoiesis may contribute to
pathogenesis [18-20] . TET2 mutations are common and may occur in almost half of AITL and over one-third of
PTCL-NOS cases . A second study showed three-quarters of patients with AITL have mutations in TET2,
[21]
[22]
with two-thirds of these cases with more than one mutation in the gene . Preclinical studies have
demonstrated a causal relationship between mutations in TET2 and the development of both lymphoid and
[17]
myeloid cancers . 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.

DNA methyltransferase 3 alpha (DNMT3A) encodes a DNA methyltransferase and is found to be mutated
[22]
in 10%-40% of AITL cases . Alterations in DNMT3A are thought to be the initial event in malignant
transformation and often occur with mutations in TET2 [22,25] . Murine models demonstrate loss-of-function
[26]
mutations in both TET2 and DNMT3A lead to lymphomagenesis .

Finally, isocitrate dehydrogenase-2 (IDH2) encodes a mitochondrial enzyme that is involved in
2-oxoglutarate generation. Mutations in IDH2 at residue 172, where arginine is replaced by other amino
[27]
acids, have been found in up to half of AITL cases . Mutant forms have altered enzymatic activity leading
to the overproduction of 2-hydroxyglutarate, an oncometabolite that antagonizes the TET family of
enzymes. Specifically, IDH2 mutations lead to altered enzyme activity that catalyzes the conversion of
[28]
α-keto glutarate (αKG) to 2-hydroxyglutarate (2HG). Elevated levels of intracellular 2HG interfere with the
conversion of the DNA base 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), which is
important in DNA demethylation. Interestingly, AITL is the only subtype of the T-cell lymphomas with
mutations in IDH2 and remarkably all the mutations occur at position R172, which is associated with
abnormally high levels of 2HG. The mutation in IDH2 (p.Arg172) leads to hypermethylation of gene
promoters in a T-cell line , consistent with a mechanism that is mediated by IDH2 and TET2 mutations,
[29]
suggesting the cause of AITL pathogenesis. As seen with alterations in DNMT3A, mutations in IDH2 appear
to occur frequently with aberrancies in TET2 .
[22]
Mutations in RhoA
RHOA is part of the Rho family of GTPases and is important in signaling pathways, such as cellular
responses and cell motility [30-32] . The role of RHOA in tumorigenesis is controversial, but cell-type-specific
functions of RHOA have recently been better defined by gene targeting techniques. Previously, there was
little understanding of RHOA in cancer pathogenesis until RHOA mutations were repeatedly reported in
AITL and PTCL NOS TFH subtypes [14,33,34] . The RHOA mutations are unique to these subtypes of PTCL,
where glycine at the 17th position is replaced by valine (G17V). RHOA G17V did not bind GTP like its
normal counterpart, but rather, it inhibited the GTP binding to wild-type RHOA. The exact biochemical
role of RHOA in T-cell signaling, however, is far from resolved. As described above, TET2 is the most
frequently mutated gene in AITL, and these tumors are commonly found to occur with RHOA G17V [14,33] .
Multiple transgenic murine models with RHOA G17V have demonstrated increased TFH proliferation as
well as an overly reactive response to T-cell receptor (TCR) stimuli [35,36] . Coupling RHOA G17V expression
with TET2 mutations resulted in the development of PTCL with TFH phenotype, i.e., AITL [36,37] . Adding