Epigenetic inactivation of DLX4 is associated with disease progression in chronic myeloid leukemia

Zhou, Jing‐Dong; Wang, Yuxin; Zhang, Ting‐Juan; Yang, Dongqin; Yao, Dong‐ming; Guo, Hong; Yang, Lei; Ma, Ji‐chun; Wen, Xiang‐mei; Yang, Jing; Jiang, Lin; Qian, Jun

doi:10.1016/j.bbrc.2015.06.095

Cited by 17 publications

(14 citation statements)

References 31 publications

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“…5A and B), whereas, the promoter of the DLX4 gene was hypermethylated compared with normal peripheral blood mobilization (day 0; Fig. 5C), which was in line with previous research which revealed that DLX4 hypermethylation was associated with disease progression in CML (8).…”

Section: Mechanisms Of Global Dna Methylation Change Induced Bysupporting

confidence: 91%

“…GDM contributed to carcinogenesis via epigenetic silencing of well-known tumor-suppressor genes (TSGs) or regulators of cell proliferation (22,23). In the present study, DLX4, a gene correlated with disease progression of CML (8), was hypermethylated during the process, which may be a pivotal regulator of the transformation.…”

Section: Discussionmentioning

confidence: 55%

“…Recently, epigenetic alterations have also been recognized as a major driving force in the development of several cancers, including leukemia (6,7). Although DNA hypermethylation of multiple genes (DLX4, SHP-1 and HOXs) characterizes advanced stages of CML and/or the disease when resistant to imatinib (8)(9)(10), the underlying epigenetic changes of DNA methylation in CML, particularly during transformation, are not fully implicated. In our previous transformation system, MVs lost their transforming abilities and the mRNA and protein of these methyltransferases decreased following…”

Section: Introductionmentioning

confidence: 99%

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The epigenetic effect of microRNA in BCR-ABL1-positive microvesicles during the transformation of normal hematopoietic transplants

Shen

Jiang

et al. 2017

Oncology Reports

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Epigenetics have been demonstrated to play a pivotal role in the progression of multiple cancers. Our previous study has demonstrated that microvesicles (MVs) derived from K562 cells could malignantly transform normal hematopoietic cells. The aim of this section was to elucidate the epigenetic effects of RNA in K562-MVs. We altered some epigenetic RNAs (miR-106a-5p, miR-106b-5p and lincPOU3F3) in K562-MVs and followed the process of transformation. Global DNA methylation and DNA methyltransferase (DNMT) levels were observed respectively. Our findings revealed that increased miR-106a/b in K562-MVs accelerated the transformation process (8.33±0.94 vs. 13.29±1.28 days; P<0.01) whereas decreased lincPOU3F3 delayed the transformation (17.83±0.29 days; P<0.05). The targets of miR-106a/b and lincPOU3F3 in the recipient cells were DNMT3a and DNMT3b. We found that lincPOU3F3 directly increased the DNMT3a/b while miR-106a/b only in part by targeting RB. However, global DNA methylation and special gene methylation was altered due to the concurrent regulation of DNMT3a and DNMT3b. Consequently, we demonstrated that tumor-derived MVs represent a notable intercellular epigenetic communication between cancer cells and recipient cells.

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Section: Mechanisms Of Global Dna Methylation Change Induced Bysupporting

confidence: 91%

Section: Discussionmentioning

confidence: 55%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The epigenetic effect of microRNA in BCR-ABL1-positive microvesicles during the transformation of normal hematopoietic transplants

Shen

Jiang

et al. 2017

Oncology Reports

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“…DLX4 is overexpressed in a wide variety of cancer types such as leukaemias and in lung, breast, ovarian and prostate cancers . To determine if there is a correlation between ablation of DLX4 function and the proliferative capacity of keratinocytes, we evaluated proliferation and migration.…”

Section: Resultsmentioning

confidence: 99%

Homeobox transcription factor DLX4 is not necessary for skin development and homeostasis

Bhattacharya

Duverger

Brooks

et al. 2018

Experimental Dermatology

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Dlx4 is a member of a family of homeobox genes with homology to Drosophila distal-less (dll) gene. We show that Dlx4 expression pattern partially overlaps with its cis-linked gene Dlx3 during mouse development as well as in neonatal and adult skin. In mice, Dlx4 is expressed in the branchial arches, embryonic limbs, digits, nose, hair follicle and in the basal and suprabasal layers of mouse interfollicular epidermis. We show that inactivation of Dlx4 in mice did not result in any overtly gross pathology. Skin development, homeostasis and response to TPA treatment were similar in mice with loss of Dlx4 compared to wild-type counterparts.

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“…This heterogeneity in disease progression is likely due to secondary chromosomal abnormalities and molecular events followed by initial BCR‐ABL translocation (Calabretta & Perrotti, ). For instance, our previous studies showed that epigenetic inactivation of distal‐less homeobox 4 ( DLX4 ) and inhibitor of DNA binding 4 ( ID4 ) was associated with disease progression in CML (Zhou et al, ; Zhou et al, ). The potential contribution of epigenetic changes, especially of long non‐coding RNAs to CML progression, has not been investigated so far.…”

Section: Introductionmentioning

confidence: 99%

Hypomethylation‐mediated H19 overexpression increases the risk of disease evolution through the association with BCR‐ABL transcript in chronic myeloid leukemia

Zhou

Jiang

Zhang

et al. 2017

Journal Cellular Physiology

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Previous study has revealed that H19 expression is required for efficient tumor growth induced by BCR-ABL in chronic myeloid leukemia (CML). Herein, we further determined H19 expression and its clinical implication in patients with CML. H19 expression and methylation were detected by real-time quantitative PCR and real-time quantitative methylation-specific PCR, and then clinical implication of H19 expression was further analyzed. H19 expression was significantly up-regulated in CML patients (p < 0.001). H19 expression with an area under receiver operating characteristic curve value of 0.824 might serve as a promising biomarker in distinguishing CML patients from controls. The patients with high H19 expression had a tendency of higher white blood cells and BCR-ABL transcript than those with low H19 expression. H19 overexpression occurred with the higher frequency in blast crisis stage (11/11, 100%), lower in accelerated phase (3/5, 60%), and chronic phase (42/62, 66%) stages. Moreover, paired patients during disease progression with increased BCR-ABL transcript also showed a significant upregulation of H19 expression. Meanwhile, H19 expression was decreased in follow-up patients who achieved complete molecular remission after tyrosine kinase inhibitors-based therapy. Epigenetic studies showed that H19 differentially methylated region/imprinting control region (DMR/ICR) was hypomethylated and associated with H19 expression in CML patients. Moreover, demethylation of H19 DMR/ICR reactivated H19 expression in K562 cells. Collectively, H19 overexpression, a frequent event in CML, was associated with higher BCR-ABL transcript involving in disease progression. Moreover, H19 DMR/ICR hypomethylation in CML may be one of the mechanisms mediating H19 overexpression.

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Epigenetic inactivation of DLX4 is associated with disease progression in chronic myeloid leukemia

Cited by 17 publications

References 31 publications

The epigenetic effect of microRNA in BCR-ABL1-positive microvesicles during the transformation of normal hematopoietic transplants

The epigenetic effect of microRNA in BCR-ABL1-positive microvesicles during the transformation of normal hematopoietic transplants

Homeobox transcription factor DLX4 is not necessary for skin development and homeostasis

Hypomethylation‐mediated H19 overexpression increases the risk of disease evolution through the association with BCR‐ABL transcript in chronic myeloid leukemia

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