Multistep tumorigenesis in peripheral T cell lymphoma

Abstract

is angioimmunoblastic T cell lymphoma (AITL) and a subtype of peripheral T cell lymphoma, not otherwise specified (PTCL-NOS) [4][5][6][7][8][9].An intriguing observation was that these mutations were detected in premalignant cells as well as tumor cells [4,5,8,[10][11][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][11][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 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.

Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell–derived lymphomas

“…5 In the proposed multistep model of pathogenesis for TFH-derived PTCL, mutation-induced epigenetic deregulation, possibly arising in early hematopoietic precursors, may promote the emergence of premalignant cells, which requires additional genetic events to acquire a definitively malignant phenotype. 13,55 It has been thus suggested that RHOA alterations occur as a second event in TET2-and/or DNMT3A-mutated cells. 13,55,56 The prevalence of mutations in TET2, DNMT3A, and IDH2 analyzed in a subset of our cases was 52% (34/65 cases), 29% (17/ 56 cases), and 30% (21/71 cases), respectively.…”

“…13,55 It has been thus suggested that RHOA alterations occur as a second event in TET2-and/or DNMT3A-mutated cells. 13,55,56 The prevalence of mutations in TET2, DNMT3A, and IDH2 analyzed in a subset of our cases was 52% (34/65 cases), 29% (17/ 56 cases), and 30% (21/71 cases), respectively. 8,9 These mutations were not mutually exclusive, and in fact tended to co-occur with each other, as previously reported.…”

Recent Progress in the Understanding of Angioimmunoblastic T-cell Lymphoma

“…31 Thus, these mutations may represent the fundamental mechanisms for hematological malignancies, although their diagnostic value for detecting these mutations is unclear.…”

“…74,75 These observations suggested that some PTCLs may originate from TET2-and DNMT3A-mutated premalignant cells. 31 RHOA and IDH2 mutations were found only in tumor cells, suggesting that these mutations are acquired in the later processes of AITL development 13,76 (Figure 2). These observations raise questions on how the tumorinfiltrating B cells are associated with clonal expansion.…”

Review of the biologic and clinical significance of genetic mutations in angioimmunoblastic T‐cell lymphoma

“…G17V RHOA mutations were commonly observed in the other nodal T‐cell lymphomas with TFH phenotype: 57%‐62% of nodal PTCL with TFH phenotype and 60% of FTCL, while they were quite rare in other diseases. In contrast, TET2 and DNMT3A mutations were found in a broad range of hematologic malignancies, and even in healthy elderly individuals . (Note: See the Section below, “.”) Among T‐cell lymphomas, TET2 mutations were more prevalent in nodal T‐cell lymphomas with TFH phenotype than those without TFH phenotype (nodal PTCL with TFH phenotype vs FTCL vs PTCL without the TFH phenotype: 64% vs 75% vs 17%) .…”