T‐cell acute lymphoblastic leukemia (T‐ALL) is an aggressive malignancy accounting for 10%–15% of pediatric and 20%–25% of adult ALL cases. Epigenetic irregularities in T‐ALL include alterations in ...both DNA methylation and the post‐translational modifications on histones which together play a critical role in the initiation and development of T‐ALL. Characterizing the oncogenic mutations that result in these epigenetic changes combined with the reversibility of epigenetic modifications represents an opportunity for the development of epigenetic therapies. Oncogenic mutations and deregulated expression of DNA methyltransferases (DNMTs), Ten‐Eleven Translocation dioxygenases (TETs), Histone acetyltransferases (HATs) and members of Polycomb Repressor Complex 2 (PRC2) have all been identified in T‐ALL. This review focuses on the current understanding of how these mutations lead to epigenetic changes in T‐ALL, their association with disease pathogenesis and the current efforts to exploit these clinically through the development of epigenetic therapies in T‐ALL treatment.
Epigenetic modifications play a crucial role in orchestrating normal T‐cell development. In the context of T‐cell acute lymphoblastic leukemia, the discovery of recurrent mutations and dysregulated expression of proteins controling DNA methylation and histone modifications provides promising new avenues for targeted therapeutic interventions.
The vertebrate Fat cadherins comprise a small gene family of four members, Fat1–Fat4, all closely related in structure to Drosophila ft and ft2. Over the past decade, knock‐out mouse studies, genetic ...manipulation, and large sequencing projects has aided our understanding of the function of vertebrate Fat cadherins in tissue development and disease. The majority of studies of this family have focused on Fat1, with evidence now showing it can bind enable (ENA)/Vasodilator‐stimulated phosphoprotein (VASP), β‐catenin and Atrophin proteins to influence cell polarity and motility; HOMER‐1 and HOMER‐3 proteins to regulate actin accumulation in neuronal synapses; and scribble to influence the Hippo signaling pathway. Fat2 and Fat3 can regulate cell migration in a tissue specific manner and Fat4 appears to influence both planar cell polarity and Hippo signaling recapitulating the activity of Drosophila ft. Knowledge about the exact downstream signaling pathways activated by each family member remains in its infancy, but it is becoming clearer that they have tissue specific and redundant roles in development and may be lost or gained in cancer. In this review, we summarize the recent progress on understanding the role of the Fat cadherin family, integrating the current knowledge of molecular interactions and tissue distributions, together with the accumulating evidence of their changed expression in human disease. The latter is now beginning to promote interest in these molecules as both biomarkers and new targets for therapeutic intervention.
Radiotherapy is essential to the treatment of most solid tumors and acquired or innate resistance to this therapeutic modality is a major clinical problem. Here we show that miR-139-5p is a potent ...modulator of radiotherapy response in breast cancer via its regulation of genes involved in multiple DNA repair and reactive oxygen species defense pathways. Treatment of breast cancer cells with a miR-139-5p mimic strongly synergized with radiation both
and
, resulting in significantly increased oxidative stress, accumulation of unrepaired DNA damage, and induction of apoptosis. Several miR-139-5p target genes were also strongly predictive of outcome in radiotherapy-treated patients across multiple independent breast cancer cohorts. These prognostically relevant miR-139-5p target genes were used as companion biomarkers to identify radioresistant breast cancer xenografts highly amenable to sensitization by cotreatment with a miR-139-5p mimetic.
The microRNA described in this study offers a potentially useful predictive biomarker of radiosensitivity in solid tumors and a generally applicable druggable target for tumor radiosensitization.
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Cellular stress can occur in many forms; oxidative stress caused by reactive oxygen species (ROS), metabolic stress from increased metabolic programs and genotoxic stress in the form of DNA damage ...and disrepair. In most instances, these different types of cell stress initiate programmed cell death. However, in cancer, cells are able to resist cellular stress and by-pass growth limiting checkpoints. Recent findings have now revealed that the large and heterogenous RNA species known as long non-coding RNAs (lncRNAs) are major players in regulating and overcoming cancer cell stress. lncRNAs constitute a significant fraction of the genes differentially expressed in response to cell stress and contribute to the management of downstream cellular processes, including the regulation of key stress responses such as metabolic stress, oxidative stress and genotoxic stress. This review highlights the complex regulatory role of lncRNAs in the cell stress response of cancer by providing an overview of key examples from recent literature.
The genetic basis of the predisposition for Down Syndrome (DS) patients to develop cytokine receptor-like factor 2 rearranged (CRLF2r) acute lymphoblastic leukemia (ALL) is currently unknown. Genes ...located on chromosome 21 and expressed in hematopoietic cells are likely candidates for investigation of CRLF2r DS-ALL pathogenesis. We explored the high-mobility group nucleosome-binding protein 1 (HMGN1), located in the DS critical region, in an inducible CRISPR/Cas9 knockout (KO) xenograft model to assess the effect of HMGN1 loss of function on the leukemic burden. We demonstrated HMGN1 KO-mitigated leukemic phenotypes including hepatosplenomegaly, thrombocytopenia, and anemia, commonly observed in leukemia patients, and significantly increased survival in vivo. HMGN1 overexpression in murine stem cells and Ba/F3 cells in vitro, in combination with P2RY8-CRLF2, resulted in cytokine-independent transformation and upregulation of cell signaling pathways associated with leukemic development. Finally, in vitro screening demonstrated successful targeting of P2RY8-CRLF2 and HMGN1 co-expressing cell lines and patient samples with fedratinib (JAK2 inhibitor), and GSK-J4 (demethylase inhibitor) in combination. Together, these data provide critical insight into the development and persistence of CRLF2r DS-ALL and identify HMGN1 as a potential therapeutic target to improve outcomes and reduce toxicity in this high-risk cohort of young patients.
T-cell acute lymphoblastic leukemia (T-ALL) is a high-risk subtype of acute lymphoblastic leukemia (ALL) with gradually improved survival through introduction of intensified chemotherapy. However, ...therapy-resistant or refractory T-ALL remains a major clinical challenge. Here, we evaluated B-cell lymphoma (BCL)-2 inhibition by the BH3 mimetic ABT-199 as a new therapeutic strategy in human T-ALL. The T-ALL cell line LOUCY, which shows a transcriptional program related to immature T-ALL, exhibited high in vitro and in vivo sensitivity for ABT-199 in correspondence with high levels of BCL-2. In addition, ABT-199 showed synergistic therapeutic effects with different chemotherapeutic agents including doxorubicin, l-asparaginase, and dexamethasone. Furthermore, in vitro analysis of primary patient samples indicated that some immature, TLX3- or HOXA-positive primary T-ALLs are highly sensitive to BCL-2 inhibition, whereas TAL1 driven tumors mostly showed poor ABT-199 responses. Because BCL-2 shows high expression in early T-cell precursors and gradually decreases during normal T-cell differentiation, differences in ABT-199 sensitivity could partially be mediated by distinct stages of differentiation arrest between different molecular genetic subtypes of human T-ALL. In conclusion, our study highlights BCL-2 as an attractive molecular target in specific subtypes of human T-ALL that could be exploited by ABT-199.
•High levels of the anti-apoptotic factor BCL-2 can be therapeutically exploited by the BH3 mimetic ABT-199 in human T-ALL.
Mucosa‐associated lymphoid tissue 1 (Malt1) regulates immune cell function by mediating the activation of nuclear factor κB (NF‐κB) signaling through both its adaptor and proteolytic function. Malt1 ...is also a target of its own protease activity and this self‐cleavage further contributes to NF‐κB activity. Until now, the functional distinction between Malt1 self‐cleavage and its general protease function in regulating NF‐κB signaling and immune activation remained unclear. Here we demonstrate, using a new mouse model, the importance of Malt1 self‐cleavage in regulating expression of NF‐κB target genes and subsequent T cell activation. Significantly, we further establish that Treg homeostasis is critically linked to Malt1 function via a Treg intrinsic and extrinsic mechanism. TCR‐mediated Malt1 proteolytic activity and self‐cleavage was found to drive Il2 expression in conventional CD4+ T cells, thereby regulating Il2 availability for Treg homeostasis. Remarkably, the loss of Malt1‐mediated self‐cleavage alone was sufficient to cause a significant Treg deficit resulting in increased anti‐tumor immune reactivity without associated autoimmunity complications. These results establish for the first time that inhibition of MALT1 proteolytic activity could be a viable therapeutic strategy to augment anti‐tumor immunity.
Genetic ablation of Malt1 self‐cleavage in transgenic mice results in decreased Il2 production and reduced regulatory T cells homeostasis. Significantly, this reduction of regulatory T cell numbers did result in an increased anti‐tumour effect due to increased immune surveillance but retains a level above the threshold that triggers autoimmunity.
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