Epigenetic aspects of MDS and its molecular targeted therapy

Yamazaki, Jumpei; Issa, Jean–Pierre J.

doi:10.1007/s12185-012-1197-4

Cited by 25 publications

(18 citation statements)

References 85 publications

(89 reference statements)

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“…Both of these findings suggest a link between iron and leukemogenesis. Concerning the mechanism, DNA methylation is considered to be associated with the pathogenesis and exacerbation of MDS [23][24][25][26][27]. In this study, we first demonstrated that iron overload activated the ACO1-IDH pathway in the TCA cycle and led to increased 2-HG activity, which induced DNA methylation, a critical epigenetic aberration process.…”

Section: Discussionmentioning

confidence: 69%

“…α-KG acts as a substrate of the TCA cycle, whereas it is utilized in many other reactions including DNA demethylation [20,21]. Recently, IDH mutation and the up-regulation of DNA methylation were also predicted to be independent prognosis factors in patients with MDS [22][23][24][25][26][27]. Therefore, the mechanism of aberrant DNA methylation in patients with MDS is to be elucidated further.…”

Section: Introductionmentioning

confidence: 99%

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Iron-induced epigenetic abnormalities of mouse bone marrow through aberrant activation of aconitase and isocitrate dehydrogenase

et al. 2016

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Iron overload remains a concern in myelodysplastic syndrome (MDS) patients. Iron chelation therapy (ICT) thus plays an integral role in the management of these patients. Moreover, ICT has been shown to prolong leukemia-free survival in MDS patients; however, the mechanisms responsible for this effect are unclear. Iron is a key molecule for regulating cytosolic aconitase 1 (ACO1). Additionally, the mutation of isocitrate dehydrogenase (IDH), the enzyme downstream of ACO1 in the TCA cycle, is associated with epigenetic abnormalities secondary to 2-hydroxyglutarate (2-HG) and DNA methylation. However, epigenetic abnormalities observed in many MDS patients occur without IDH mutation. We hypothesized that iron itself activates the ACO1-IDH pathway, which may increase 2-HG and DNA methylation, and eventually contribute to leukemogenesis without IDH mutation. Using whole RNA sequencing of bone marrow cells in iron-overloaded mice, we observed that the enzymes, phosphoglucomutase 1, glycogen debranching enzyme, and isocitrate dehydrogenase 1 (Idh1), which are involved in glycogen and glucose metabolism, were increased. Digital PCR further showed that Idh1 and Aco1, enzymes involved in the TCA cycle, were also elevated. Additionally, enzymatic activities of TCA cycle and methylated DNA were increased. Iron chelation reversed these phenomena. In conclusion, iron activation of glucose metabolism causes an increase of 2-HG and DNA methylation.

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Section: Discussionmentioning

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Iron-induced epigenetic abnormalities of mouse bone marrow through aberrant activation of aconitase and isocitrate dehydrogenase

et al. 2016

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“…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

Int J Hematol

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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.

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“…Multiple signals are involved in the dysregulation of hematopoiesis and evolution of MDS [1]–[3]. Major components include altered methylation status of double stranded DNA and histones.…”

Section: Introductionmentioning

confidence: 99%

The KDM2B- Let-7b -EZH2 Axis in Myelodysplastic Syndromes as a Target for Combined Epigenetic Therapy

et al. 2014

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Both DNA and histone methylation are dysregulated in the myelodysplastic syndromes (MDS). Based on preliminary data we hypothesized that dysregulated interactions of KDM2B, let-7b and EZH2 signals lead to an aberrant epigenetic landscape. Gene expression in CD34+ cells from MDS marrows was analyzed by NanoString miR array and validated by real-time polymerase chain reaction (PCR). The functions of KDM2B, let-7b and EZH2 were characterized in myeloid cell lines and in primary MDS cells. Let-7b levels were significantly higher, and KDM2B and EZH2 expression was lower in primary CD34+ MDS marrow cells (n = 44) than in healthy controls (n = 21; p<0.013, and p<0.0001, respectively). Overexpression of let-7b reduced EZH2 and KDM2B protein levels, and decreased cells in S-phase while increasing G0/G1 cells (p = 0.0005), accompanied by decreased H3K27me3 and cyclin D1. Silencing of KDM2B increased let-7b expression. Treatment with the cyclopentanyl analog of 3-deazaadenosine, DZNep, combined with the DNA hypomethylating agent 5-azacitidine, decreased levels of EZH2, suppressed methylation of di- and tri-methylated H3K27, and increased p16 expression, associated with cell proliferation. Thus, KDM2B, via let-7b/EZH2, promotes transcriptional repression. DZNep bypassed the inhibitory KDM2B/let-7b/EZH2 axis by preventing H3K27 methylation and reducing cell proliferation. DZNep might be able to enhance the therapeutic effects of DNA hypomethylating agents such as 5-azacitidine, currently considered standard therapy for patients with MDS.

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Epigenetic aspects of MDS and its molecular targeted therapy

Cited by 25 publications

References 85 publications

Iron-induced epigenetic abnormalities of mouse bone marrow through aberrant activation of aconitase and isocitrate dehydrogenase

Iron-induced epigenetic abnormalities of mouse bone marrow through aberrant activation of aconitase and isocitrate dehydrogenase

Multistep tumorigenesis in peripheral T cell lymphoma

The KDM2B- Let-7b -EZH2 Axis in Myelodysplastic Syndromes as a Target for Combined Epigenetic Therapy

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