Epigenetic dysregulation of hematopoietic stem cells and preleukemic state

Kunimoto, Hiroyoshi; Nakajima, Hitoshi

doi:10.1007/s12185-017-2257-6

Cited by 23 publications

(20 citation statements)

References 101 publications

(149 reference statements)

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“…In fact, some studies have identified aberrant methylomes in adult patients with MDS, as well as hypermethylation of specific genes, particularly during the course of AML. 10,12,17,26,31 In our results, we observed an association between p15 INK4B promoter methylation and higher DNMT1 expression levels. In this way, it is possible that DNMT3A and DNMT3B produce new methylation patterns during the development of the MDS and that DNMT1 acts by maintaining these patterns.…”

Section: Discussionsupporting

confidence: 68%

“…The first involves the progressive oxidation of 5-methylcytosine (5mC) and is catalysed by the teneleven-translocation (TET) family of enzymes; the second is driven by the apolipoprotein B mRNA editing enzyme (APOBECs) family, which deaminates 5mC and 5-hydroxylmethyl cytosine (5hmC). [17][18][19] In both cases, mispairing takes place and the base excision repair machinery replaces the modified base by an unmethylated cytosine. 18 The balance between the enzymes that act on DNA methylation and demethylation is essential for the maintenance of genomic stability and is referred to as the DNA methylation and demethylation machinery.…”

Section: Introductionmentioning

confidence: 99%

“…21 Even in adult patients, few studies have been performed to analyse the expression of DNA methylation and demethylation machinery components. 17,22 Although the APOBEC family is an important component in the demethylation machinery 18,19 and APOBEC3B has been described as a driving mutagenic agent during cancer development and progression, 23 no studies involving the APOBEC family have been performed in MDS. Thus, the aim of this study was to analyse the expression of DNMT1, DNMT3A, DNMT3B (components of the DNA methylation machinery), TET2 and APOBEC3B (components of the DNA demethylation machinery) in pediatric patients with MDS and investigate their associations with MDS subtypes, cytogenetics, evolution to AML and the p15 INK4B methylation levels of gene to verify the role of epigenetic alterations during pediatric MDS pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

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<p>Expression Profiles of DNA Methylation and Demethylation Machinery Components in Pediatric Myelodysplastic Syndrome: Clinical Implications</p>

Lovatel¹,

Fernandez²,

Rodrigues³

et al. 2020

CMAR

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The aim of this study was to analyse the expression profiles of DNMT1, DNMT3A, DNMT3B (components of DNA methylation machinery), TET2 and APOBEC3B (components of DNA demethylation machinery) in pediatric MDS patients and investigate their associations with MDS subtypes, cytogenetics, evolution to acute myeloid leukemia (AML) and p15 INK4B methylation level. Patients and Methods: The expressions of DNMT1, DNMT3A, DNMT3B, TET2, and APOBEC3B were evaluated in 39 pediatric MDS patients by real-time quantitative PCR (qPCR). The quantification of p15 INK4B methylation levels (MtL) was performed in 20 pediatric MDS patients by pyrosequencing. Mann-Whitney test was used to evaluate possible differences between the expression levels of selected in patients and donors, according to MDS subtypes, karyotypes, evolution to AML and p15 INK4B MtL. The correlations between the expression levels of the different genes were assessed by Spearman rank correlation coefficient. Results: We found that DNMTs expression levels were higher in pediatric MDS compared to donors [DNMT1 (p<0.03), DNMT3A (p<0.03), DNMT3B (p<0.02)]. TET2 and APOBEC3B expression levels did not show a statistically significant difference between pediatric patients and donors. Considering MDS subtypes, patients at initial stage presented DNMT1 overexpression (p<0.01), while DNMT3A (p<0.02) and DNMT3B (p<0.007) were overexpressed in advanced subtypes. TET2 and APOBEC3B expression did not differ in MDS subtypes. DNMT1 (p<0.03), DNMT3B (p<0.03), and APOBEC3B (p<0.04) expression was higher in patients with normal karyotypes, while patients with abnormal karyotypes showed higher DNMT3A expression (p<0.03). Karyotypes had no association with TET2 expression. DNMTs overexpression was observed in patients who showed disease evolution. A positive correlation was found between DNMTs expression and between APOBEC3B and DNMT3A/DNMT3B. However, TET2 expression was not correlated with DNMTs or APOBEC3B. p15 INK4B MtL was higher in pediatric MDS patients compared with donors (p<0.03) and its hypermethylation was associated with increased DNMT1 expression (p<0.009). Conclusion: Our results suggest that the overexpression of DNMTs and an imbalance between the expressions of the DNA methylation/demethylation machinery components play an important role in MDS development and evolution to AML. These results have clinical implications indicating the importance of DNMTs inhibitors for preventing or delaying the progression to leukemia in pediatric MDS patients.

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Section: Discussionsupporting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

<p>Expression Profiles of DNA Methylation and Demethylation Machinery Components in Pediatric Myelodysplastic Syndrome: Clinical Implications</p>

Lovatel¹,

Fernandez²,

Rodrigues³

et al. 2020

CMAR

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“…Though chemotherapeutic agents, molecular targeted drugs, and hematopoietic stem cell transplantation have shown therapeutic efficacy in AML, many patients still relapse [2][3][4]. Nowadays, epigenetic alterations are becoming increasingly valued for their contribution to hematopoietic transformation likely by providing growth advantages and altering expression of cancer specification genes [3,5]. Therefore, a deep understanding of epigenetic mechanisms and dysregulations in AML will become a priority in biomedical research.…”

Section: Introductionmentioning

confidence: 99%

miR-362-5p promotes cell proliferation and cell cycle progression by targeting GAS7 in acute myeloid leukemia

Chen

et al. 2020

Human Cell

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Recently, miR-362-5p has attracted special interest as a novel prognostic predictor in acute myeloid leukemia (AML). However, its biological function and underlying molecular mechanism in AML remain to be further defined. Herein, we found that a significant increase in miR-362-5p expression was observed in AML patients and cell lines using quantitative realtime PCR. The expression of miR-362-5p was altered in THP-1 and HL-60 cells by transfecting with miR-362-5p mimic or inhibitor. A series of experiments showed that inhibition of miR-362-5p expression significantly suppressed cell proliferation, induced G0/G1 phase arrest and attenuated tumor growth in vivo. On the contrary, ectopic expression of miR-362-5p resulted in enhanced cell proliferation, cell cycle progression and tumor growth. Moreover, growth arrest-specific 7 (GAS7) was confirmed as a direct target gene of miR-362-5p and was negatively modulated by miR-362-5p. GAS7 overexpression imitated the tumor suppressive effect of silenced miR-362-5p on THP-1 cells. Furthermore, miR-362-5p knockdown or GAS7 overexpression obviously down-regulated the expression levels of PCNA, CDK4 and cyclin D1, but up-regulated p21 expression. Collectively, our findings demonstrate that miR-362-5p exerts oncogenic effects in AML by directly targeting GAS7, which might provide a promising therapeutic target for AML.

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“… 43 , 44 The analysis of large sets of older people of different geographical regions without evidence of hematologic malignancies has confirmed a high incidence of clonal hematopoiesis (5%–10% at 70 years; about 20% at 90 years), and has shown that the most commonly mutated genes are DNMT3A , TET2 , and ASXL1 . 45 , 46 …”

Section: Introductionmentioning

confidence: 99%

Targeting histone methyltransferase and demethylase in acute myeloid leukemia therapy

Castelli¹,

Pelosi²,

Testa³

2017

OTT

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Acute myeloid leukemia (AML) is a clonal disorder of myeloid progenitors characterized by the acquisition of chromosomal abnormalities, somatic mutations, and epigenetic changes that determine a consistent degree of biological and clinical heterogeneity. Advances in genomic technologies have increasingly shown the complexity and heterogeneity of genetic and epigenetic alterations in AML. Among the genetic alterations occurring in AML, frequent are the genetic alterations at the level of various genes involved in the epigenetic control of the DNA methylome and histone methylome. In fact, genes involved in DNA demethylation (such as DNMT3A, TET2, IDH1, and IDH2) or histone methylation and demethylation (EZH2, MLL, DOT1L) are frequently mutated in primary and secondary AML. Furthermore, some histone demethylases, such as LSD1, are frequently overexpressed in AML. These observations have strongly supported a major role of dysregulated epigenetic regulatory processes in leukemia onset and development. This conclusion was further supported by the observation that mutations in genes encoding epigenetic modifiers, such as DMT3A, ASXL1, TET2, IDH1, and IDH2, are usually acquired early and are present in the founding leukemic clone. These observations have contributed to development of the idea that targeting epigenetic abnormalities could represent a potentially promising strategy for the development of innovative treatments of AML. In this review, we analyze those proteins and their inhibitors that have already reached the first stages of clinical trials in AML, namely the histone methyltransferase DOT1L, the demethylase LSD1, and the MLL-interacting protein menin.

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Epigenetic dysregulation of hematopoietic stem cells and preleukemic state

Abstract: decipher the exact mechanism by which preleukemic stem cells originate and transform into a full-blown leukemic state.

Cited by 23 publications

References 101 publications

<p>Expression Profiles of DNA Methylation and Demethylation Machinery Components in Pediatric Myelodysplastic Syndrome: Clinical Implications</p>

<p>Expression Profiles of DNA Methylation and Demethylation Machinery Components in Pediatric Myelodysplastic Syndrome: Clinical Implications</p>

miR-362-5p promotes cell proliferation and cell cycle progression by targeting GAS7 in acute myeloid leukemia

Targeting histone methyltransferase and demethylase in acute myeloid leukemia therapy

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