Effects of TET2 mutations on DNA methylation in chronic myelomonocytic leukemia

Section: Tet2mentioning

confidence: 95%

Epigenetic dysregulation of hematopoietic stem cells and preleukemic state

Kunimoto

Nakajima

2017

“…Ko et al [49] reported a subset of genes with hypomethylation in CMML patients with TET2 mutations. However, our data recently suggested that effects of TET2 mutations on DNA methylation are primarily outside both CGI and promoters ( [50] and in submission). These findings may provide further understanding of CMML leukemogenesis and could lead to the development of new strategies for CMML patients.…”

Section: Epigenetic Changes In Mdsmentioning

confidence: 83%

“…Using a promoter-array for methylation analysis, a smaller number of hypomethylation sites was observed compared to hypermethylation sites in MDS [46]. A recent report showed frequent promoter hypomethylation in TET2 mutant CMML cases [49], though this was not consistently found in other studies [50]. Extensive genome-wide analysis will be required to study global hypomethylation in MDS occurs to the same extent as in the other cancers.…”

Section: Epigenetic Changes In Mdsmentioning

confidence: 97%

Epigenetic aspects of MDS and its molecular targeted therapy

Yamazaki

Issa

2012

Self Cite

The term ''epigenetics'' refers to clonally inherited stable variability in gene expression without underlying genetic changes. There are two well-known molecular mechanisms for epigenetic information: DNA methylation and histone modifications. Epigenetic changes have been recognized in the past decade as critical factors for physiological phenomena such as embryogenesis and the differentiation of normal cells. There is recent interest regarding the involvement of aberrant DNA methylation and histone modifications in mediating altered physiology in cancer. MDS is characterized by epigenetic changes, mutations in epigenetic regulators, and response to DNA methylation inhibitors, suggesting that epigenetic changes are unique features of MDS patients. In this article, recent progress in the understanding of MDS epigenetics and epigenetics-based therapies is reviewed.

“…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][42][43][44][45]. It is controversial whether the functional impairment of TET2/DNMT3A results in hypermethylation/hypomethylation [2,[41][42][43][44][45][46][47], respectively.…”

Section: Clonal Evolution Of Mutation-bearing Prelymphoma Cellsmentioning

confidence: 99%

“…Epigenetic profiles of TET2-or -DNMT3A-mutated tumors in myeloid malignancies have been studied by several groups [41][42][43][44][45]. It is controversial whether the functional impairment of TET2/DNMT3A results in hypermethylation/hypomethylation [2,[41][42][43][44][45][46][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].…”

Section: Clonal Evolution Of Mutation-bearing Prelymphoma Cellsmentioning

confidence: 99%

Multistep tumorigenesis in peripheral T cell lymphoma

Sakata‐Yanagimoto

2015

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.