Abstract
Peripheral T cell lymphomas (PTCL) are classified as mature T cell neoplasms. However, several new findings support the notion that premalignant cells arise in the immature stage of hematopoietic differentiation, and subsequently evolve into full-blown T-lineage tumor cells. Acquisition of (Ten-Eleven Translocation 2) TET2 mutations may be an important event for the establishment of premalignant cells. In PTCL harboring features of follicular helper T cells, tumor-specific G17V RHOA mutations co-occur with premalignant TET2 mutations. The G17V (ras homolog family member A) RHOA mutations may play important roles in clonal evolution of premalignant cells into tumor cells. Indeed, multistep tumorigenesis is thought to be essential for pathogenesis of PTCL.
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Introduction
Recent advances in sequencing technologies led to the discovery of gene mutations in epigenetic regulators, including Ten-Eleven Translocation 2 (TET2) [1], DNA methyltransferase 3A (DNMT3A) [2], and isocitrate dehydrogenase 1 /2 (IDH1/2) [3] in hematologic malignancies. These gene mutations were first identified in myeloid malignancies [1–3]. Subsequently, they were also found in lymphoid malignancies [4–6]. The mutation frequencies were especially high in peripheral T cell lymphoma (PTCL) with features of follicular helper T (Tfh) cells, that is angioimmunoblastic T cell lymphoma (AITL) and a subtype of peripheral T cell lymphoma, not otherwise specified (PTCL-NOS) [4–9].
An intriguing observation was that these mutations were detected in premalignant cells as well as tumor cells [4, 5, 8, 10–12]. Additionally, distinct mutations for each disease were found in the full-blown tumor cells [8, 10, 12]. That is, the stepwise accumulation of mutations might contribute to the development of tumor cells. This review will especially focus on the multistep tumorigenesis in PTCL from a genetic point of view.
Origins of TET2 and DNMT3A mutations in PTCL
In some cases of PTCL, TET2 and DNMT3A mutations were identified not only in the T-lineage tumor cells but also in non-tumor hematopoietic cells, including B and myeloid cells as well as myeloid progenitors [4, 5, 8]. These data suggest that the mutations occurred in hematopoietic stem/multipotent hematopoietic progenitors in PTCL [4, 5, 8]. In other words, the origins of PTCL are in the immature stage of hematopoietic differentiation although the full-blown tumor cells have characteristics of terminally differentiated T-lineage cells.
TET2 and DNMT3A mutations were also detected in apparently normal hematopoietic stem cells (HSCs) in the leukemic phase and those at the remission state in acute myeloid leukemia (AML) [10–12]. Occasionally, both lymphoid and myeloid malignancies occurred simultaneously or serially in a patient. It has been reported that identical TET2 and/or DNMT3A mutations were detected in specimens of each disease in a case with B-cell lymphoma and AML [4], and cases with AITL and myelodysplastic syndrome [5]. These data further support the notion that TET2 and DNMT3A mutations may reside in premalignant cells in a wide variety of hematopoietic malignancies in addition to PTCL.
During the aging process, a part of the blood system, especially the myeloid compartment, is occasionally replaced by cells originating from a clone [13, 14]. The mechanisms of clonal hematopoiesis are yet to be elucidated. Darwinism may explain why it occurs; one cell obtains advantages for survival over other cells; then, selection pressure accelerates substitution in the blood system by its clones.
Remarkably, TET2 mutations were observed in 5.6 % of normal elderly individuals with non-random X-chromosome inactivation [16]. TET2-mutant allele burden revealed close concordance with the degree of skewing determined by the X-inactivation patterns [15]. It means that TET2-mutant allele burden might reflect the clonal size of blood cells [15]. Subsequently, recurrent mutations in DNMT3A as well as other leukemia and/or lymphoma-associated genes were also reported in the blood cells of elderly individuals without hematologic malignancies [16–18]. The allele frequencies of the mutations were low in a substantial number of cases, possibly in the early stages of clonal expansion [16].
The functions of TET2 and DNMT3A genes in the blood system have been extensively examined in knockout mouse studies. It has been reported by several groups that deletion of TET2 in mice leads to an increase in the self-renewal capacity of hematopoietic stem cells (HSC) [4, 19–22]. Deletion of DNMT3A also enhances the self-renewal capacity, while it markedly inhibits cellular differentiation [23].
Given the results of knockout mouse experiments, functional impairment of TET2 or DNMT3A by gene mutations would give superiority to the mutation-bearing cells over non-mutated cells, and contribute to the establishment of clonal hematopoiesis during aging. Finally, the mutation-bearing hematopoietic progenitors may evolve into preleukemic/prelymphoma stem cells (Fig. 1). In fact, the presence of somatic mutations in the blood was associated with significantly higher risk of hematologic malignancies [17, 18], while impact of these mutations on incidence of PTCL remains to be elucidated.
Multistep tumorigenesis in PTCL. TET2- or DNMT3A- mutated hematopoietic progenitors evolve into preleukemic/prelymphoma stem cells. Both myeloid and lymphoid malignancies can emerge from the preleukemic/lymphoma cells. Subsequent genetic events determine the cell fate of preleukemic/prelymphoma cells
Clonal evolution of mutation-bearing prelymphoma cells
Both myeloid and lymphoid malignancies can emerge from TET2-or DNMT3A-mutated preleukemic/lymphoma stem cells (Fig. 1). So, what kinds of mechanisms are required for the development of each disease?
Gene mutations in myeloid malignancies have been extensively analyzed since the 1980s. First, mutations in neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) were discovered in myelodysplastic syndrome in 1987 [24]. Subsequently, mutations in fms-related tyrosine kinase3 (FLT3) [25], CCAAT/enhancer binding protein (C/EBP), alpha [26], and nucleophosmin (NPM1) [27] were identified in AML. To date, mutations have been identified in more than 100 genes [28–30], most of which are known to be essential in the differentiation and proliferation/apoptosis of myeloid cells.
In contrast, the mutational profiles of PTCL were not elucidated until very recently. By comprehensive gene-mutation analysis, we and others found novel recurrent mutations in ras homolog family member A (RHOA) in PTCL with features of Tfh cells: 53–71 % of AITL [8, 9, 31] and 62 % of AITL-like PTCL-NOS [8]. Most of the RHOA mutations found in PTCL were confined to c. 50G>T, resulting in conversion from glycine to valine at the 17th position of the RHOA protein (G17V RHOA) [8, 9, 31].
RHOA mutations were also reported in 8.5 % of Burkitt lymphoma, though the distribution of mutations was different from those in PTCL [32]. The RHOA mutations in Burkitt lymphoma were concentrated at c.14C>G, resulting in conversion from arginine to glutamine at the 5th position, while G17V RHOA mutations were not detected [32]. Also, G17V RHOA mutations were not detected in myeloid malignancies or other B-cell malignancies in our cohort [8].
Remarkably, the RHOA-mutated samples had the TET2 mutations [8]. The coexistence of the RHOA and TET2 mutations suggests that the crosstalk of these mutations might contribute to the pathogenesis of AITL.
As described, TET2 mutations existed in the preleukemic/prelymphoma cells. The allele frequencies of the RHOA mutations were statistically lower than those of the TET2 mutations in the samples with both mutations [8]. These data suggest that the G17V RHOA mutations occurred later than the TET2 mutations. Furthermore, RHOA mutations were not detected in the non-tumor hematopoietic cells, whereas TET2 mutations were detected both in tumor cells and non-tumor hematopoietic cells [8].
From these pieces of genetic evidence, it seems likely that G17V RHOA mutations play a main role in the development of PTCL with features of Tfh cells. The G17V RHOA mutations in TET2-mutated prelymphoma cells may facilitate the selective differentiation of these cells into Tfh-like tumor cells (Fig. 1).
Functions of the G17V RHOA mutants
As described above, RHOA mutations might play an essential role in the multistep tumorigenesis of PTCL [8]. RHOA is a small GTPase, cycling between an active GTP-bound state and an inactive GDP-bound state [33]. The activation of RHOA is mediated by guanine exchange factors (GEFs) [33]. The G17V RHOA mutant cannot bind GTP and exhibits defective RHOA signaling in the cells [8, 9, 31]. The roles of the G17V RHOA mutant in AITL development have not been clarified. Inhibition of RHOA signaling by expressing C3 transferase, an inhibitor of RHO signaling under the lck promoter, was reported to provoke fatal T cell malignancies in mice [34].
Recently, frequent RHOA mutations were reported in diffuse-type gastric cancers [35–37]. The RHOA mutations in gastric cancers resulted in defective RHOA signaling in the cells [37], although the hotspot sites of RHOA mutations in gastric cancers were different from those in AITL [35–37]. Genetic alterations of RHOA might have functional properties for cancer development greater than expected.
Coexistence of TET2 and DNMT3A mutations in prelymphoma cells
Eventually, both of TET2 and DNMTA, frequently mutated in prelymphoma cells in PTCL, encode DNA modifying enzymes. The downstream molecular events of these mutations in prelymphoma cells are unclear.
TET2 encodes a methylcytosine dioxygenase, converting methylcytosine to hydroxymethylcytosine, formylcytosine, and carboxylcytosine [38–40]. One of the functions of TET2 protein is thought to be to mediate the demethylation process. On the other hand, DNMT3A encodes a methylcytosine transferase, converting cytosine to methylcytosine. Considering the physiological functions of these epigenetic regulators, loss-of-function mutations in these genes might have the opposite roles in the DNA methylation process. Epigenetic profiles of TET2- or -DNMT3A-mutated tumors in myeloid malignancies have been studied by several groups [41–45]. It is controversial whether the functional impairment of TET2/DNMT3A results in hypermethylation/hypomethylation [ 2, 41–47], respectively. Namely, the samples with TET2 mutations had hypermethylation profiles in some reports [42, 44, 45], while opposite results were reported in others [41, 43]. In parallel, differential methylation patterns, either hypomethylation or hypermethylation, were observed in more than 3000 genomic regions between those with or without DNMT3A mutations in one report [46], while DNMT3A mutations were associated with hypomethylation in less than 200 genomic regions in another report [2]. Furthermore, it is more complicated for understanding that TET2 and DNMT3A mutations are simultaneously identified in a substantial number of samples in both PTCL [8, 9] and myeloid malignancies [28, 48, 49]. Until now, there are no reports describing impact of TET2/DNMT3A mutations on methylation status in PTCL.
IDH2 mutations; their origins and correlations with TET2 mutations
IDH2 mutations were detected in both PTCL and myeloid malignancies although the hotspots differed among the diseases. In PTCL, the mutations were restricted to those affecting the R172 position [6, 8, 9], while both R140 and R172 mutations were found in myeloid malignancies [28, 50]. Moreover, mutations in the IDH1 gene, another member of the IDH family, were detected in AML at similar frequencies to those of the IDH2 mutations [50], while they have been rarely identified in PTCL [5, 6, 8 ]. IDH2 and TET2 mutations are known to be exclusive in myeloid malignancies [42, 49, 51]. This is explained by the hypothesis that 2-hydroxyglutarate, which is produced by the IDH2 mutant, is known to inhibit the function of alpha-ketoglutarate (alpha-KG)-dependent dioxygenases, including the TET2 protein [42, 52]. As a result, the IDH1/2-mutated and the TET2-mutated myeloid malignancies were reported to have similar hypermethylation patterns [42]. In contrast, IDH2 mutations were detected in a part of the RHOA-TET2 mutated samples in PTCL [8]. The coexistence of IDH2 and TET2 mutations in PTCL suggests that the downstream mechanisms of IDH2 mutations in PTCL might be different from those in myeloid malignancies (Fig. 2).
Relationship between IDH2 and TET2 mutations in hematologic malignancies. IDH2 and TET2 mutations are known to be exclusive in myeloid malignancies, because the IDH2 mutants contribute to myeloid malignancies through inhibition of TET2 function. The coexistence of IDH2 and TET2 mutations in PTCL suggests that the targets of the IDH2 mutants in PTCL might be different from those in myeloid malignancies
It has been reported that IDH2 mutations existed in preleukemic cells in AML [10, 12]. In PTCL, the allele frequencies of IDH2 mutations were much lower than those of TET2 mutations, suggesting that IDH2 mutations occur later than TET2 mutations [8]. In addition, IDH2 mutations were not detected in non-tumor hematopoietic cells in PTCL [8]. These data suggest that the IDH2 mutations are a relatively late event in most PTCL cases.
The specific inhibitors for IDH mutants have been developed and are now under clinical trial in AML [53]. Considering the different distribution of IDH2 mutations in AML and PTCL, the clinical significance of the IDH inhibitors should be independently examined in PTCL.
Conclusion
For more than 20 years PTCLs have been thought to be mature T cell malignancies. However, the origins of PTCLs can be tracked back to the immature stage of hematopoiesis. Specific genetic events contribute to clonal evolution of prelymphoma cells into characteristic tumor cells. Understanding multistep tumorigenesis in PTCL will enable us to find new strategies for treating such dire diseases.
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