The synergistic proapoptotic effect of PARP-1 and HDAC inhibition in cutaneous T-cell lymphoma is mediated via Blimp-1

Kruglov, Oleg; Wu, Xuesong; Hwang, Samuel T; Akilov, Oleg E.

doi:10.1182/bloodadvances.2020002049

Cited by 15 publications

(14 citation statements)

References 37 publications

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“…HDACi therapy has already been shown to have positive effects on aggressive CTCL types. HDACis in combination with other therapy, such as chemotherapeutic drugs, immunomodulatory drugs, monoclonal antibody, may provide a novel treatment option that can improve clinical outcomes in patients with CTCL ( 34 , 35 , 57 , 70 , 131 – 133 ) ( Table 2 ). Currently, more and more HDACI combination therapy regimens are undergoing clinical trials, indicating the important role of HDACi drug in the treatment of CTCL.…”

Section: Discussionmentioning

confidence: 99%

Epigenetics in the Pathogenesis and Treatment of Cutaneous T-Cell Lymphoma

Zhang

2021

Front. Oncol.

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Cutaneous T-cell lymphomas (CTCLs) comprise a group of heterogeneous diseases involving malignant T cells. The pathogenesis and etiology of CTCL are still unclear, although a large number of genetic and epidemiological studies on CTCL have been conducted. Most CTCLs have an indolent course, making early diagnosis difficult. Once large-cell transformation occurs, CTCL progresses to more aggressive types, resulting in an overall survival of less than five years. Epigenetic drugs, which have shown certain curative effects, have been selected as third-line drugs in patients with relapsing and refractory CTCL. Many studies have also identified epigenetic biomarkers from tissues and peripheral blood of patients with CTCL and suggested that epigenetic changes play a role in malignant transformation and histone deacetylase inhibitor (HDACi) resistance in CTCL. Single-cell sequencing has been applied in CTCL studies, revealing heterogeneity in CTCL malignant T cells. The mechanisms of HDACi resistance have also been described, further facilitating the discovery of novel HDACi targets. Despite the heterogeneity of CTCL disease and its obscure pathogenesis, more epigenetic abnormalities have been gradually discovered recently, which not only enables us to understand CTCL disease further but also improves our understanding of the specific role of epigenetics in the pathogenesis and treatment. In this review, we discuss the recent discoveries concerning the pathological roles of epigenetics and epigenetic therapy in CTCL.

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Section: Discussionmentioning

confidence: 99%

Epigenetics in the Pathogenesis and Treatment of Cutaneous T-Cell Lymphoma

Zhang

2021

Front. Oncol.

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“…Kruglov et al. reported that Parp1 inhibition increased the expression of Irf8 and Bcl6 , leading to upregulation of Blimp1 and Bax and subsequently restraining DNA repair in cutaneous T cell lymphoma ( Kruglov et al., 2020 ). Another study reported that Bcl6 directly regulates Bach2 expression and Ung expression ( Alinikula et al., 2011 ).…”

Section: Discussionmentioning

confidence: 99%

Bach2 Deficiency Promotes Intestinal Epithelial Regeneration by Accelerating DNA Repair in Intestinal Stem Cells

Rao

Tang

et al. 2021

Stem Cell Reports

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Summary Epithelial regeneration is critical for barrier maintenance and organ function after intestinal injury, although the repair mechanisms are unclear. Here, we found that Bach2 deficiency promotes intestinal epithelial cell proliferation during homeostasis. Moreover, genetic inactivation of Bach2 in mouse intestinal epithelium facilitated crypt regeneration after irradiation, resulting in a reduction in mortality. RNA-sequencing analysis of isolated crypts revealed that Bach2 deficiency altered the expression of numerous genes, including those regulating double-strand break repair. Mechanistic characterizations indicated that Bach2 deletion facilitated DNA repair in intestinal crypt cells, as evidenced by faster resolution of γ-H2AX and 53BP1 foci in Bach2 −/− crypt cells, compared with Bach2 +/+ control. Together, our studies highlight that Bach2 deficiency promotes intestinal regeneration by accelerating DNA repair in intestinal stem cells after radiation damage.

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“…The model is largely inflammation dependent, and resolution of inflammation leads to the resolution of lymphoma. While BALB/c mice do not support implantation of MBL2 tumors, B6.SJL mice can be easily inoculated with MBL2 without underlying inflammatory microenvironment (Table 2) [74,[81][82][83]. Mishra et al, (2016) evaluated the role of an inflammatory cytokine IL-15 in CTCL using IL-15 transgenic (Tg) mice that developed skin inflammation with some features reminiscent of human MF.…”

Section: Gemm and Other Important Ctcl Mouse Modelsmentioning

confidence: 99%

Understanding Cell Lines, Patient-Derived Xenograft and Genetically Engineered Mouse Models Used to Study Cutaneous T-Cell Lymphoma

Gill

Gantchev

Villarreal

et al. 2022

Cells

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Cutaneous T cell lymphoma (CTCL) is a spectrum of lymphoproliferative disorders caused by the infiltration of malignant T cells into the skin. The most common variants of CTCL include mycosis fungoides (MF), Sézary syndrome (SS) and CD30+ Lymphoproliferative disorders (CD30+ LPDs). CD30+ LPDs include primary cutaneous anaplastic large cell lymphoma (pcALCL), lymphomatoid papulosis (LyP) and borderline CD30+ LPD. The frequency of MF, SS and CD30+ LPDs is ~40–50%, <5% and ~10–25%, respectively. Despite recent advances, CTCL remains challenging to diagnose. The mechanism of CTCL carcinogenesis still remains to be fully elucidated. Hence, experiments in patient-derived cell lines and xenografts/genetically engineered mouse models (GEMMs) are critical to advance our understanding of disease pathogenesis. To enable this, understanding the intricacies and limitations of each individual model system is highly important. Presently, 11 immortalized patient-derived cell lines and different xenograft/GEMMs are being used to study the pathogenesis of CTCL and evaluate the therapeutic efficacy of various treatment modalities prior to clinical trials. Gene expression studies, and the karyotyping analyses of cell lines demonstrated that the molecular profile of SeAx, Sez4, SZ4, H9 and Hut78 is consistent with SS origin; MyLa and HH resemble the molecular profile of advanced MF, while Mac2A and PB2B represent CD30+ LPDs. Molecular analysis of the other two frequently used Human T-Cell Lymphotropic Virus-1 (HTLV-1)+ cell lines, MJ and Hut102, were found to have characteristics of Adult T-cell Leukemia/Lymphoma (ATLL). Studies in mouse models demonstrated that xenograft tumors could be grown using MyLa, HH, H9, Hut78, PB2B and SZ4 cells in NSG (NOD Scid gamma mouse) mice, while several additional experimental GEMMs were established to study the pathogenesis, effect of drugs and inflammatory cytokines in CTCL. The current review summarizes cell lines and xenograft/GEMMs used to study and understand the etiology and heterogeneity of CTCL.

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The synergistic proapoptotic effect of PARP-1 and HDAC inhibition in cutaneous T-cell lymphoma is mediated via Blimp-1

Cited by 15 publications

References 37 publications

Epigenetics in the Pathogenesis and Treatment of Cutaneous T-Cell Lymphoma

Epigenetics in the Pathogenesis and Treatment of Cutaneous T-Cell Lymphoma

Bach2 Deficiency Promotes Intestinal Epithelial Regeneration by Accelerating DNA Repair in Intestinal Stem Cells

Understanding Cell Lines, Patient-Derived Xenograft and Genetically Engineered Mouse Models Used to Study Cutaneous T-Cell Lymphoma

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