S860 TARGETING ABERRANT DNA METHYLATION AS A NOVEL AND UNIFORM THERAPEUTIC STRATEGY FOR THE TREATMENT OF T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA AND LYMPHOMA

Distinct DNA methylation signatures, related to different prognosis, have been observed across many cancers, including T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematological neoplasm. By global methylation analysis, two major phenotypes might be observed in T-ALL: hypermethylation related to better outcome and hypomethylation, which is a candidate marker of poor prognosis. Moreover, DNA methylation holds more than a clinical meaning. It reflects the replicative history of leukemic cells and most likely different mechanisms underlying leukemia development in these T-ALL subtypes. The elucidation of the mechanisms and aberrations specific to (epi-)genomic subtypes might pave the way towards predictive diagnostics and precision medicine in T-ALL. We present the current state of knowledge on the role of DNA methylation in T-ALL. We describe the involvement of DNA methylation in normal hematopoiesis and T-cell development, focusing on epigenetic aberrations contributing to this leukemia. We further review the research investigating distinct methylation phenotypes in T-ALL, related to different outcomes, pointing to the most recent research aimed to unravel the biological mechanisms behind differential methylation. We highlight how technological advancements facilitated broadening the perspective of the investigation into DNA methylation and how this has changed our understanding of the roles of this epigenetic modification in T-ALL.

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Targeting calcineurin activation as a therapeutic strategy for T-cell acute lymphoblastic leukemia

Yearbook of Dermatology and Dermatologic Surgery ◽

10.1016/s0093-3619(08)70711-1 ◽

2008 ◽

Vol 2008 ◽

pp. 57-58

Author(s):

B.H. Thiers

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Therapeutic Strategy ◽

Lymphoblastic Leukemia ◽

Cell Acute Lymphoblastic Leukemia

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DNA methylation-based classification reveals difference between pediatric T-cell acute lymphoblastic leukemia and normal thymocytes

Leukemia ◽

10.1038/s41375-019-0626-2 ◽

2019 ◽

Vol 34 (4) ◽

pp. 1163-1168 ◽

Cited By ~ 2

Author(s):

Shunsuke Kimura ◽

Masafumi Seki ◽

Tomoko Kawai ◽

Hiroaki Goto ◽

Kenichi Yoshida ◽

...

Keyword(s):

Dna Methylation ◽

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Lymphoblastic Leukemia ◽

Cell Acute Lymphoblastic Leukemia

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DNA Methylation Adds Prognostic Value to Minimal Residual Disease Status in Pediatric T‐Cell Acute Lymphoblastic Leukemia

Pediatric Blood & Cancer ◽

10.1002/pbc.25958 ◽

2016 ◽

Vol 63 (7) ◽

pp. 1185-1192 ◽

Cited By ~ 13

Author(s):

Magnus Borssén ◽

Zahra Haider ◽

Mattias Landfors ◽

Ulrika Norén‐Nyström ◽

Kjeld Schmiegelow ◽

...

Keyword(s):

Dna Methylation ◽

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Minimal Residual Disease ◽

Prognostic Value ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Disease Status ◽

Cell Acute Lymphoblastic Leukemia ◽

Minimal Residual

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Targeting calcineurin activation as a therapeutic strategy for T-cell acute lymphoblastic leukemia

Nature Medicine ◽

10.1038/nm1588 ◽

2007 ◽

Vol 13 (6) ◽

pp. 736-741 ◽

Cited By ~ 101

Author(s):

Hind Medyouf ◽

Hélène Alcalde ◽

Caroline Berthier ◽

Marie Claude Guillemin ◽

Nuno R dos Santos ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Therapeutic Strategy ◽

Lymphoblastic Leukemia ◽

Cell Acute Lymphoblastic Leukemia

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DNA Methylation-Mediated Silencing of Mir-204 Enhances the Occurrence of T-Cell Acute Lymphoblastic Leukemia By Upregulating MMP-2 and MMP-9 through the NF-Κb Signaling Pathway

Blood ◽

10.1182/blood-2020-142386 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 11-11

Author(s):

Dabing Chen ◽

Tingting Xiao ◽

Dandan Lin ◽

Haojie Zhu ◽

Jingjing Xu ◽

...

Keyword(s):

Dna Methylation ◽

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Matrix Metalloproteinase ◽

Western Blot ◽

Signaling Pathway ◽

Promoter Region ◽

Lymphoblastic Leukemia ◽

Cell Acute Lymphoblastic Leukemia

Background : MicroRNAs (miR) are non-coding RNAs that play a role in regulation multiple functions in different cell types. Previous studies have shown that miR-204 is downregulated in T-ALL. We previously reported that matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) gene polymorphisms may be associated with the risk of T-cell acute lymphoblastic leukemia (T-ALL). The present study aims to decipher the role of miR-204 and MMP-2/MMP-9 in T-ALL occurrence to guide the diagnosis and treatment of T-ALL in the clinics. Methods: Expression of miR-204 was determined in the bone marrow and peripheral blood samples from 70 T-ALL patients and 70 healthy volunteers by real-time quantitative PCR (RT-qPCR). Bisulfite sequencing PCR (BSP) was used to detect the DNA methylation levels of the miR-204 promoter region in T-ALL patients and T-ALL cell lines.The effect of miR-204 on cell proliferation was evaluated with the cell counting kit-8 solution (CCK-8) assay and by Hoechst and PI double staining. The binding site of miR-204 on IRAK1 was predicted by the Primer Premier 5.0 and the defined binding sequences were used to construct luciferase-tag plasmids. The regulation of IRAK1 expression by miR-204 was evaluated by RT-qPCR and Western blot analysis. With the purpose to confirm the role of MMP-2 and MMP-9 in the occurrence of T-ALL, we investigated the effect of related proteins on T-ALL cells using Western blot. To determine that miR-204 affects the occurrence of T-ALL disease by regulating the NF-KB signaling pathway, RT-qPCR and Western Blot were used for verification. Results: DNA methylation directly affects the miR-204 expression in the promoter region when T-ALL developed. Moreover, overexpression of miR-204 inhibited the proliferation and enhanced the apoptosis of T-ALL cells. Notably, overexpression of miR-204 inhibited IRAK1, which in turn inhibited the proliferation and enhanced the apoptosis of T-ALL cells. Furthermore, IRAK1 enhanced the expression of MMP-2 and MMP-9 through phosphorylation of of p65 NF-κB, and miR-204 modulated MMP-2 and MMP-9 expression through the IRAK1/NF-κB signaling pathway. Conclusion s : Our results demonstrate that in T-ALL cells, DNA methylation-mediated silencing of miR-204 regulates the expression of MMP-2 and MMP-9 through increased transcription of IRAK1, and activation of the NF-κB signaling pathway. These data provide a potential mechanism for the role of MMP-2 and MMP-9 in the occurrence of T-ALL. Further studies will be needed to demonstrate whether demethylation of miR-204 may be a promising treatment for T-ALL. Disclosures No relevant conflicts of interest to declare.

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