Epigenetics in T‐cell acute lymphoblastic leukemia

Peirs, Sofie; Meulen, Joni Van der; Walle, Inge Van de; Taghon, Tom; Speleman, Franki; Poppe, Bruce; Vlierberghe, Pieter Van

doi:10.1111/imr.12237

Cited by 65 publications

(55 citation statements)

References 176 publications

(289 reference statements)

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“…In T-cell acute lymphoid leukemia (T-ALL) several types of oncogenes are involved in leukemogenesis deregulating survival, proliferation and developmental processes, resulting in differentiation arrest of developing T-cells at particular stages [1–3]. T-cell differentiation is mainly regulated at the transcriptional level creating gene regulatory networks [4].…”

Section: Introductionmentioning

confidence: 99%

Deregulation of polycomb repressor complex 1 modifier AUTS2 in T-cell leukemia

et al. 2016

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Recently, we identified deregulated expression of the B-cell specific transcription factor MEF2C in T-cell acute lymphoid leukemia (T-ALL). Here, we performed sequence analysis of a regulatory upstream section of MEF2C in T-ALL cell lines which, however, proved devoid of mutations. Unexpectedly, we found strong conservation between the regulatory upstream region of MEF2C (located at chromosomal band 5q14) and an intergenic stretch at 7q11 located between STAG3L4 and AUTS2, covering nearly 20 kb. While the non-coding gene STAG3L4 was inconspicuously expressed, AUTS2 was aberrantly upregulated in 6% of T-ALL patients (public dataset GSE42038) and in 3/24 T-ALL cell lines, two of which represented very immature differentiation stages. AUTS2 expression was higher in normal B-cells than in T-cells, indicating lineage-specific activity in lymphopoiesis. While excluding chromosomal aberrations, examinations of AUTS2 transcriptional regulation in T-ALL cells revealed activation by IL7-IL7R-STAT5-signalling and MEF2C. AUTS2 protein has been shown to interact with polycomb repressor complex 1 subtype 5 (PRC1.5), transforming this particular complex into an activator. Accordingly, expression profiling and functional analyses demonstrated that AUTS2 activated while PCGF5 repressed transcription of NKL homeobox gene MSX1 in T-ALL cells. Forced expression and pharmacological inhibition of EZH2 in addition to H3K27me3 analysis indicated that PRC2 repressed MSX1 as well. Taken together, we found that AUTS2 and MEF2C, despite lying on different chromosomes, share strikingly similar regulatory upstream regions and aberrant expression in T-ALL subsets. Our data implicate chromatin complexes PRC1/AUTS2 and PRC2 in a gene network in T-ALL regulating early lymphoid differentiation.

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Section: Introductionmentioning

confidence: 99%

Deregulation of polycomb repressor complex 1 modifier AUTS2 in T-cell leukemia

et al. 2016

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“…A significant number of T-ALL patients show poor responses to treatment. Compared with the more common B-cell-lineage ALL, T-ALL is defined by distinct clinical and biological characteristics and is generally associated with more unfavorable clinical features [3]. T-ALL can be subdivided into different stages depending on different markers (CD3, CD7, CD28, CD1a, CD34, CD4 and CD8) expressed in the T cells.…”

Section: Introductionmentioning

confidence: 99%

miR-125b regulates differentiation and metabolic reprogramming of T cell acute lymphoblastic leukemia by directly targeting A20

et al. 2016

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T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic malignancy. Although it has been reported that overexpression of miR-125b leads to T-ALL development, the underlying mechanisms of miR-125b action are still unclear. The goal of this study is to delineate the role of miR-125b in T-ALL development. We found that miR-125b is highly expressed in undifferentiated leukemic T cells (CD4-negative) while its expression is low in differentiated T cells (CD4-positive). Overexpression of miR-125b increased the CD4-negative population in T cells, whereas depletion of miR-125b by miR-125b-sponge decreased the CD4-negative cell population. We identified that A20 (TNFAIP3) is a direct target of miR-125b in T cells. Overexpression of miR-125b also increased glucose uptake and oxygen consumption in T cells through targeting A20. Furthermore, restoration of A20 in miR-125b-overexpressing cells decreased the CD4-negative population in T cell leukemia, and decreased glucose uptake and oxygen consumption to the basal level of T cells transfected with vector. In conclusion, our data demonstrate that miR-125b regulates differentiation and reprogramming of T cell glucose metabolism via targeting A20. Since both de-differentiation and dysregulated glucose metabolism contribute to the development of T-cell leukemia, these findings provide novel insights into the understanding and treatment of T-ALL.

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“…T-cell acute lymphoblastic leukemia is a type of cancer with a high frequency of mutations in genes encoding for epigenetic regulators, which suggests a therapeutic potential of epigenetic drugs for the treatment of this hematologic malignancy [22]. We have recently described the induction of apoptosis by the nucleosides analogues decitabine and zebularine in leukemic T cells [23].…”

Section: Introductionmentioning

confidence: 99%

The antihypertensive drug hydralazine activates the intrinsic pathway of apoptosis and causes DNA damage in leukemic T cells

et al. 2016

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Epigenetic therapies have emerged as promising anticancer approaches, since epigenetic modifications play a major role in tumor initiation and progression. Hydralazine, an approved vasodilator and antihypertensive drug, has been recently shown to act as a DNA methylation inhibitor. Even though hydralazine is already tested in clinical cancer trials, its mechanism of antitumor action remains undefined. Here, we show that hydralazine induced caspase-dependent apoptotic cell death in human p53-mutant leukemic T cells. Moreover, we demonstrate that hydralazine triggered the mitochondrial pathway of apoptosis by inducing Bak activation and loss of the mitochondrial membrane potential. Hydralazine treatment further resulted in the accumulation of reactive oxygen species, whereas a superoxide dismutase mimetic inhibited hydralazine-induced cell death. Interestingly, caspase-9-deficient Jurkat cells or Bcl-2- and Bcl-xL-overexpressing cells were strongly resistant to hydralazine treatment, thereby demonstrating the dependence of hydralazine-induced apoptosis on the mitochondrial death pathway. Furthermore, we demonstrate that hydralazine treatment triggered DNA damage which might contribute to its antitumor effect.

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Epigenetics in T‐cell acute lymphoblastic leukemia

Cited by 65 publications

References 176 publications

Deregulation of polycomb repressor complex 1 modifier AUTS2 in T-cell leukemia

Deregulation of polycomb repressor complex 1 modifier AUTS2 in T-cell leukemia

miR-125b regulates differentiation and metabolic reprogramming of T cell acute lymphoblastic leukemia by directly targeting A20

The antihypertensive drug hydralazine activates the intrinsic pathway of apoptosis and causes DNA damage in leukemic T cells

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