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Multiple myeloma is a hematological malignancy arising from immunoglobulin-secreting plasma cells. It remains poorly understood how chromatin rewiring of regulatory elements contributes to tumorigenesis and therapy resistance in myeloma. Here we generate a high-resolution contact map of myeloma-associated super-enhancers by integrating H3K27ac ChIP-seq and HiChIP from myeloma cell lines, patient-derived myeloma cells and normal plasma cells. Our comprehensive transcriptomic and phenomic analyses prioritize candidate genes with biological and clinical implications in myeloma. We show that myeloma cells frequently acquire SE that transcriptionally activate an oncogene PPP1R15B, which encodes a regulatory subunit of the holophosphatase complex that dephosphorylates translation initiation factor eIF2α. Epigenetic silencing or knockdown of PPP1R15B activates pro-apoptotic eIF2α-ATF4-CHOP pathway, while inhibiting protein synthesis and immunoglobulin production. Pharmacological inhibition of PPP1R15B using Raphin1 potentiates the anti-myeloma effect of bortezomib. Our study reveals that myeloma cells are vulnerable to perturbation of PPP1R15B-dependent protein homeostasis, highlighting a promising therapeutic strategy. The role of chromatin rewiring of regulatory elements in multiple myeloma (MM) remains poorly understood. Here, the authors identify a super-enhancer driven gene, PPP1R15B whose perturbation confers vulnerability in MM cells and suggest it as a therapeutic target. [ABSTRACT FROM AUTHOR]

Background: Extranodal natural killer/T-cell lymphoma (NKTL) is an aggressive type of non-Hodgkin lymphoma with dismal outcome. A better understanding of disease biology and key oncogenic process is necessary for the development of targeted therapy. Super-enhancers (SEs) have been shown to drive pivotal oncogenes in various malignancies. However, the landscape of SEs and SE-associated oncogenes remain elusive in NKTL. Methods: We used Nano-ChIP-seq of the active enhancer marker histone H3 lysine 27 acetylation (H3K27ac) to profile unique SEs NKTL primary tumor samples. Integrative analysis of RNA-seq and survival data further pinned down high value, novel SE oncogenes. We utilized shRNA knockdown, CRISPR-dCas9, luciferase reporter assay, ChIP-PCR to investigate the regulation of transcription factor (TF) on SE oncogenes. Multi-color immunofluorescence (mIF) staining was performed on an independent cohort of clinical samples. Various function experiments were performed to evaluate the effects of TOX2 on the malignancy of NKTL in vitro and in vivo. Results: SE landscape was substantially different in NKTL samples in comparison with normal tonsils. Several SEs at key transcriptional factor (TF) genes, including TOX2, TBX21(T-bet), EOMES, RUNX2, and ID2, were identified. We confirmed that TOX2 was aberrantly overexpressed in NKTL relative to normal NK cells and high expression of TOX2 was associated with worse survival. Modulation of TOX2 expression by shRNA, CRISPR-dCas9 interference of SE function impacted on cell proliferation, survival and colony formation ability of NKTL cells. Mechanistically, we found that RUNX3 regulates TOX2 transcription by binding to the active elements of its SE. Silencing TOX2 also impaired tumor formation of NKTL cells in vivo. Metastasis-associated phosphatase PRL-3 has been identified and validated as a key downstream effector of TOX2-mediated oncogenesis. Conclusions: Our integrative SE profiling strategy revealed the landscape of SEs, novel targets and insights into molecular pathogenesis of NKTL. The RUNX3-TOX2-SE-TOX2-PRL-3 regulatory pathway may represent a hallmark of NKTL biology. Targeting TOX2 could be a valuable therapeutic intervene for NKTL patients and warrants further study in clinic. [ABSTRACT FROM AUTHOR]

The transcription factor MYB is a crucial regulator of hematopoietic stem and progenitor cells. However, the nature of lineage-specific enhancer usage of the Myb gene is largely unknown. We identify the Myb −68 enhancer, a regulatory element which marks basophils and mast cells. Using the Myb −68 enhancer activity, we show a population of granulocyte-macrophage progenitors with higher potential to differentiate into basophils and mast cells. Single cell RNA-seq demonstrates the differentiation trajectory is continuous from progenitors to mature basophils in vivo, characterizes bone marrow cells with a gene signature of mast cells, and identifies LILRB4 as a surface marker of basophil maturation. Together, our study leads to a better understanding of how MYB expression is regulated in a lineage-associated manner, and also shows how a combination of lineage-related reporter mice and single-cell transcriptomics can overcome the rarity of target cells and enhance our understanding of gene expression programs that control cell differentiation in vivo. The transcription factor MYB has been shown to regulate haematopoietic stem cells but there could be lineage specific enhancers. Here, using lineage tracing and single cell sequencing the authors characterise a Myb −68 enhancer that regulates the differentiation of mast cells and basophils. [ABSTRACT FROM AUTHOR]

Simple Summary: Master transcription factors regulate essential developmental processes and cellular maintenance that characterize cell identity. Many of them also serve as oncogenes when aberrantly expressed or activated. IRF4 is one of prime examples of oncogenic master transcription factors that has been implicated in various mature lymphoid neoplasms. IRF4 forms unique regulatory circuits and induces oncogenic transcription programs through the interactions with upstream pathways and binding partners. IRF4 is a transcription factor in the interferon regulatory factor (IRF) family. Since the discovery of this gene, various research fields including immunology and oncology have highlighted the unique characteristics and the importance of IRF4 in several biological processes that distinguish it from other IRF family members. In normal lymphocyte development and immunity, IRF4 mediates critical immune responses via interactions with upstream signaling pathways, such as the T-cell receptor and B-cell receptor pathways, as well as their binding partners, which are uniquely expressed in each cell type. On the other hand, IRF4 acts as an oncogene in various mature lymphoid neoplasms when abnormally expressed. IRF4 induces several oncogenes, such as MYC, as well as genes that characterize each cell type by utilizing its ability as a master regulator of immunity. IRF4 and its upstream factor NF-κB form a transcriptional regulatory circuit, including feedback and feedforward loops, to maintain the oncogenic transcriptional program in malignant lymphoid cells. In this review article, we provide an overview of the molecular functions of IRF4 in mature lymphoid neoplasms and highlight its upstream and downstream pathways, as well as the regulatory circuits mediated by IRF4. [ABSTRACT FROM AUTHOR]

IRF4 is a master regulator of immunity and is also frequently overexpressed in mature lymphoid neoplasms. Here, we demonstrate the oncogenicity of IRF4 in vivo, its potential effects on T-cell development and clonal evolution using a zebrafish model. IRF4-transgenic zebrafish develop aggressive tumors with massive infiltration of abnormal lymphocytes that spread to distal organs. Many late-stage tumors are mono- or oligoclonal, and tumor cells can expand in recipient animals after transplantation, demonstrating their malignancy. Mutation of p53 accelerates tumor onset, increases penetrance, and results in tumor heterogeneity. Surprisingly, single-cell RNA-sequencing reveals that the majority of tumor cells are double-negative T-cells, many of which express tcr-γ that became dominant as the tumors progress, whereas double-positive T-cells are largely diminished. Gene expression and epigenetic profiling demonstrates that gata3, mycb, lrrn1, patl1 and psip1 are specifically activated in tumors, while genes responsible for T-cell differentiation including id3 are repressed. IRF4-driven tumors are sensitive to the BRD inhibitor. IRF4 is a regulator of immune function, and is overexpressed in lymphoid neoplasms. Here, the authors utilise single cell RNA-seq to show the abundance of double-negative T cells in IRF4 driven zebrafish tumour models, and identify sensitivity of these tumours to BRD inhibition. [ABSTRACT FROM AUTHOR]

Background: Acute lymphoblastic leukemia (ALL) is the most common cancer in children and can arise in B or T lymphoid lineages. Although risk loci have been identified for B-ALL, the inherited basis of T-ALL is mostly unknown, with a particular paucity of genome-wide investigation of susceptibility variants in large patient cohorts.Methods: We performed a genome-wide association study (GWAS) in 1191 children with T-ALL and 12 178 controls, with independent replication using 117 cases and 5518 controls. The associations were tested using an additive logistic regression model. Top risk variants were tested for effects on enhancer activity using luciferase assay. All statistical tests were two sided.Results: A novel risk locus in the USP7 gene (rs74010351, odds ratio [OR] = 1.44, 95% confidence interval [CI] = 1.27 to 1.65, P = 4.51 × 10-8) reached genome-wide significance in the discovery cohort, with independent validation (OR = 1.51, 95% CI = 1.03 to 2.22, P = .04). The USP7 risk allele was overrepresented in individuals of African descent, thus contributing to the higher incidence of T-ALL in this race/ethnic group. Genetic changes in USP7 (germline variants or somatic mutations) were observed in 56.4% of T-ALL with TAL1 overexpression, statistically significantly higher than in any other subtypes. Functional analyses suggested this T-ALL risk allele is located in a putative cis-regulatory DNA element with negative effects on USP7 transcription. Finally, comprehensive comparison of 14 susceptibility loci in T- vs B-ALL pointed to distinctive etiology of these leukemias.Conclusions: These findings indicate strong associations between inherited genetic variation and T-ALL susceptibility in children and shed new light on the molecular etiology of ALL, particularly commonalities and differences in the biology of the two major subtypes (B- vs T-ALL). [ABSTRACT FROM AUTHOR]

Neuroblastoma originates from developing neural crest and can interconvert between the mesenchymal (MES) and adrenergic (ADRN) states, each of which are controlled by different sets of transcription factors forming the core regulatory circuit (CRC). However, the roles of CRC factors in induction and maintenance of specific state are poorly understood. Here, we demonstrate that overexpression of ASCL1, an ADRN CRC factor, in MES neuroblastoma cells opens closed chromatin at the promoters of key ADRN genes, accompanied by epigenetic activation and establishment of enhancer-promoter interactions, initiating the ADRN gene expression program. ASCL1 inhibits the transforming growth factor β-SMAD2/3 pathway but activates the bone morphogenetic protein SMAD1-ID3/4 pathway. ASCL1 and other CRC members potentiate each other's activity, increasing the expression of the original targets and inducing a new set of genes, thereby fully inducing the ADRN program. Our results demonstrate that ASCL1 serves as a pioneer factor and cooperates with CRC factors to characterize the ADRN gene expression program. [Display omitted] • ASCL1 functions as a pioneer factor that can alter the chromatin state • ASCL1 initiates ADRN gene expression program in MES neuroblastoma • ASCL1 potentiates the activities of other members of CRC • ASCL1 forms a complex with TCF12 and activates the BMP-SMAD1-ID3/4 pathway Wang et al. demonstrate that ASCL1 initiated phenotypic changes toward ADRN lineage by altering the chromatin landscape via pioneer factor function in neuroblastoma cells. The authors further show that ASCL1 collaborated with other CRC members during induction and maintenance of specific cellular state. [ABSTRACT FROM AUTHOR]

TAL1/SCL is a prime example of an oncogenic transcription factor that is abnormally expressed in acute leukemia due to the replacement of regulator elements. This gene has also been recognized as an essential regulator of hematopoiesis. TAL1 expression is strictly regulated in a lineage- and stage-specific manner. Such precise control is crucial for the switching of the transcriptional program. The misexpression of TAL1 in immature thymocytes leads to a widespread series of orchestrated downstream events that affect several different cellular machineries, resulting in a lethal consequence, namely T-cell acute lymphoblastic leukemia (T-ALL). In this article, we will discuss the transcriptional regulatory network and downstream target genes, including protein-coding genes and non-coding RNAs, controlled by TAL1 in normal hematopoiesis and T-cell leukemogenesis. [ABSTRACT FROM AUTHOR]

Activation of tyrosine kinase 2 (TYK2) contributes to the aberrant survival of T-cell acute lymphoblastic leukaemia (T-ALL) cells. Here we demonstrate the anti-leukaemic activity of a novel TYK2 inhibitor, NDI-031301. NDI-031301 is a potent and selective inhibitor of TYK2 that induced robust growth inhibition of human T-ALL cell lines. NDI-031301 treatment of human T-ALL cell lines resulted in induction of apoptosis that was not observed with the JAK inhibitors tofacitinib and baricitinib. Further investigation revealed that NDI-031301 treatment uniquely leads to activation of three mitogen-activated protein kinases (MAPKs), resulting in phosphorylation of ERK, SAPK/JNK and p38 MAPK coincident with PARP cleavage. Activation of p38 MAPK occurred within 1 h of NDI-031301 treatment and was responsible for NDI-031301-induced T-ALL cell death, as pharmacological inhibition of p38 MAPK partially rescued apoptosis induced by TYK2 inhibitor. Finally, daily oral administration of NDI-031301 at 100 mg/kg bid to immunodeficient mice engrafted with KOPT-K1 T-ALL cells was well tolerated, and led to decreased tumour burden and a significant survival benefit. These results support selective inhibition of TYK2 as a promising potential therapeutic strategy for T-ALL. [ABSTRACT FROM AUTHOR]

Novel Strategies to Screen Drugs for Molecular Targeting in Neuroblastoma Experimental Models Wong et al. attempted to integrate profiling of copy number variations (CNVs) in neuroblastoma with drug screening of corresponding patient-derived cell culture models to exploit personalized therapy. These characteristics suggest that neuroblastoma patients with poor prognosis might be in an immunosuppressed state and may offer promise for improving immunotherapy for neuroblastoma. Keywords: neuroblastoma; epigenetic regulation; noncoding RNA (ncRNA); copy number variation (CNV); intracranial metastasis (IM) EN neuroblastoma epigenetic regulation noncoding RNA (ncRNA) copy number variation (CNV) intracranial metastasis (IM) 1 2 2 03/07/22 20220304 NES 220304 Unfavorable neuroblastoma subtypes with poor survival, because of treatment resistance and metastatic spread, underscore the need for alternative diagnostic and therapeutic approaches. [Extracted from the article]

Tumour oncogenes include transcription factors that co-opt the general transcriptional machinery to sustain the oncogenic state, but direct pharmacological inhibition of transcription factors has so far proven difficult. However, the transcriptional machinery contains various enzymatic cofactors that can be targeted for the development of new therapeutic candidates, including cyclin-dependent kinases (CDKs). Here we present the discovery and characterization of a covalent CDK7 inhibitor, THZ1, which has the unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7. Cancer cell-line profiling indicates that a subset of cancer cell lines, including human T-cell acute lymphoblastic leukaemia (T-ALL), have exceptional sensitivity to THZ1. Genome-wide analysis in Jurkat T-ALL cells shows that THZ1 disproportionally affects transcription of RUNX1 and suggests that sensitivity to THZ1 may be due to vulnerability conferred by the RUNX1 super-enhancer and the key role of RUNX1 in the core transcriptional regulatory circuitry of these tumour cells. Pharmacological modulation of CDK7 kinase activity may thus provide an approach to identify and treat tumour types that are dependent on transcription for maintenance of the oncogenic state. [ABSTRACT FROM AUTHOR]

This study explored the anti-leukaemic efficacy of novel irreversible inhibitors of the major nuclear export receptor, chromosome region maintenance 1 ( CRM1, also termed XPO1). We found that these novel CRM1 antagonists, termed SINE (Selective Inhibitors of Nuclear Export), induced rapid apoptosis at low nanomolar concentrations in a panel of 14 human T-cell acute lymphoblastic leukaemia ( T- ALL) cell lines representing different molecular subtypes of the disease. To assess in vivo anti-leukaemia cell activity, we engrafted immunodeficient mice intravenously with the human T- ALL MOLT-4 cells, which harbour activating mutations of NOTCH1 and NRAS as well as loss of function of the CDKN2 A, PTEN and TP53 tumour suppressors and express a high level of oncogenic transcription factor TAL1. Importantly, we examined the in vivo anti-leukaemic efficacy of the clinical SINE compound KPT-330 against T- ALL and acute myeloid leukaemia ( AML) cells. These studies demonstrated striking in vivo activity of KPT-330 against T- ALL and AML cells, with little toxicity to normal murine haematopoietic cells. Taken together, our results show that SINE CRM1 antagonists represent promising 'first-in-class' drugs with a novel mechanism of action and wide therapeutic index, and imply that drugs of this class show promise for the targeted therapy of T- ALL and AML. [ABSTRACT FROM AUTHOR]

Although the treatment of acute myeloid leukemia (AML) has improved substantially in the past three decades, more than half of all patients develop disease that is refractory to intensive chemotherapy. Functional genomics approaches offer a means to discover specific molecules mediating the aberrant growth and survival of cancer cells. Thus, using a loss-of-function RNA interference genomic screen, we identified the aberrant expression of hepatocyte growth factor (HGF) as a crucial element in AML pathogenesis. We found HGF expression leading to autocrine activation of its receptor tyrosine kinase, MET, in nearly half of the AML cell lines and clinical samples we studied. Genetic depletion of HGF or MET potently inhibited the growth and survival of HGF-expressing AML cells. However, leukemic cells treated with the specific MET kinase inhibitor crizotinib developed resistance resulting from compensatory upregulation of HGF expression, leading to the restoration of MET signaling. In cases of AML where MET is coactivated with other tyrosine kinases, such as fibroblast growth factor receptor 1 (FGFR1), concomitant inhibition of FGFR1 and MET blocked this compensatory HGF upregulation, resulting in sustained logarithmic cell killing both in vitro and in xenograft models in vivo. Our results show a widespread dependence of AML cells on autocrine activation of MET, as well as the key role of compensatory upregulation of HGF expression in maintaining leukemogenic signaling by this receptor. We anticipate that these findings will lead to the design of additional strategies to block adaptive cellular responses that drive compensatory ligand expression as an essential component of the targeted inhibition of oncogenic receptors in human cancers. [ABSTRACT FROM AUTHOR]

A growing body of evidence indicates that early mitotic inhibitor 1 (Emi1) is essential for genomic stability, but how this function relates to embryonic development and cancer pathogenesis remains unclear. We have identified a zebrafish mutant line in which deficient emi1 gene expression results in multilineage hematopoietic defects and widespread developmental defects that are p53 independent. Cell cycle analyses of Emi1-depleted zebrafish or human cells showed chromosomal rereplication, and metaphase preparations from mutant zebrafish embryos revealed rereplicated, unsegregated chromosomes and polyploidy. Furthermore, EMI1-depleted mammalian cells relied on topoisomerase IIα-dependent mitotic decatenation to progress through metaphase. Interestingly, the loss of a single emi1 allele in the absence of p53 enhanced the susceptibility of adult fish to neural sheath tumorigenesis. Our results cast Emi1 as a critical regulator of genomic fidelity during embryogenesis and suggest that the factor may act as a tumor suppressor. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) remains an incurable disease and further development of novel agents is needed. Because constitutive expression of topoisomerase I (TopoI) in MM cells and the efficacy of SN-38, an active metabolite of irinotecan (CPT-11), have been reported, we investigated the therapeutic potential of CPT-11. Of the eight MM cell lines analyzed, four showed 50% inhibitory concentration values of less than 2 µg/mL for CPT-11 and less than 2 ng/mL for SN-38. This efficacy was partly explained by the high expression level of human carboxylesterase-2 (hCE-2) in MM cells. Interestingly, high expression of hCE-2 represented the nature of normal plasma cells, suggesting that hCE-2 could efficiently generate SN-38 within the plasma cells. As expected, higher sensitivity to CPT-11 was observed in hCE-2-overexpressing U266 cells than mock U266 cells. On the other hand, the expression levels of hCE-1, TopoI, UGT1A and ABCG2 did not seem to be associated with the sensitivity of MM cells to CPT-11. In a murine xenograft model inoculated s.c. with RPMI8226 cells, administration of CPT-11 alone significantly reduced the tumor volume. When a combination of CPT-11 and bortezomib was administered, the subcutaneous tumors completely disappeared. Thus, clinical trials on CPT-11 in patients with relapsed or refractory MM are warranted. ( Cancer Sci 2008; 99: 2309–2314) [ABSTRACT FROM AUTHOR]

Neuroblastoma, an embryonal tumour of the peripheral sympathetic nervous system, accounts for approximately 15% of all deaths due to childhood cancer. High-risk neuroblastomas are rapidly progressive; even with intensive myeloablative chemotherapy, relapse is common and almost uniformly fatal. Here we report the detection of previously unknown mutations in the ALK gene, which encodes a receptor tyrosine kinase, in 8% of primary neuroblastomas. Five non-synonymous sequence variations were identified in the kinase domain of ALK, of which three were somatic and two were germ line. The most frequent mutation, F1174L, was also identified in three different neuroblastoma cell lines. ALK complementary DNAs encoding the F1174L and R1275Q variants, but not the wild-type ALK cDNA, transformed interleukin-3-dependent murine haematopoietic Ba/F3 cells to cytokine-independent growth. Ba/F3 cells expressing these mutations were sensitive to the small-molecule inhibitor of ALK, TAE684 (ref. 4). Furthermore, two human neuroblastoma cell lines harbouring the F1174L mutation were also sensitive to the inhibitor. Cytotoxicity was associated with increased amounts of apoptosis as measured by TdT-mediated dUTP nick end labelling (TUNEL). Short hairpin RNA (shRNA)-mediated knockdown of ALK expression in neuroblastoma cell lines with the F1174L mutation also resulted in apoptosis and impaired cell proliferation. Thus, activating alleles of the ALK receptor tyrosine kinase are present in primary neuroblastoma tumours and in established neuroblastoma cell lines, and confer sensitivity to ALK inhibition with small molecules, providing a molecular rationale for targeted therapy of this disease. [ABSTRACT FROM AUTHOR]

Aberrant activation of transcription factors is frequently observed in lymphoid malignancies. Chromosomal abnormalities, genetic mutations, and/or activation of upstream molecules induce ectopic activation of transcription factors, which can remodel intracellular states by deregulating gene expression. A number of studies have shown that aberrant activity of transcription factors plays a crucial role in oncogenesis. Recent reports on specific inhibitors suggest that transcription factors could be feasible therapeutic targets. In this review, I describe the implications of transcription factors in oncogenesis as well as novel therapeutic approaches based on our previous findings including nuclear factor-κB inhibitor, synthetic retinoid, and histone deacetylase inhibitor. [ABSTRACT FROM AUTHOR]

A 55-year-old woman with Ph-negative acute lymphoblastic leukemia in primary induction failure received allogeneic peripheral blood stem cell transplantation from her HLA-compatible sister. Pseudohyponatremia developed due to extreme hypercholesterolemia of 4091 mg/dL accompanied by lipoprotein X and lipoprotein Y. The hypercholesterolemia was caused by cholestasis due to chronic GVHD and ischemic cholangiopathy. In addition, we found that hepatic triglyceride lipase (HTGL) activity was severely decreased, which could be another novel factor causing extreme hypercholesterolemia after allogeneic transplantation. The total cholesterol has been gradually decreasing followed by the improvement of cholestasis with bezafibrate, ursodeoxycholic acid and prednisone treatments, and by a slight increase in HTGL-protein. To our knowledge, this is the first report to describe the association of decreased HTGL with extreme hypercholesterolemia after allogeneic transplantation. [ABSTRACT FROM AUTHOR]

RNA helicase A (RHA), a member of DNA and RNA helicase family containing ATPase activity, is involved in many steps of gene expression such as transcription and mRNA export. RHA has been reported to bind directly to the transcriptional coactivator, CREB-binding protein, and the tumor suppressor protein, BRCA1, and links them to RNA Polymerase II holoenzyme complex.Using yeast twohybrid screening, we have identified RHA as an interacting molecule of the p65 subunit of nuclear factor κB (NF-κB). The interaction between p65 and RHA was confirmed by glutathione-Stransferase pull-down assay in vitro, and by coimmunoprecipitation assay in vivo. In transient transfection assays, RHA enhanced NF-κB dependent reporter gene expression induced by p65, tumor necrosis factor-α, or NFκB inducing kinase. Themutant form ofRHAlackingATPbinding activity inhibited NF-κB dependent reporter gene expression induced by these activators. Moreover, depletion of RHA using short interfering RNA reduced the NF-κB dependent transactivation. These data suggest that RHA is an essential component of the transactivation complex by mediating the transcriptional activity of NF-κB. [ABSTRACT FROM AUTHOR]

Nasal natural killer (NK)/T-cell lymphoma is characterized by an aggressive clinical course and poor prognosis. The term "NK/T-cell" lymphoma includes both the NK-cell type and the T-cell type, which are classified by immunophenotyping and according to T-cell receptor (TCR) rearrangement. In addition, CD56+ T-cell lymphoma is defined as NK-like T-cell lymphoma. This report concerns a 54-year-old woman with nasal T-cell lymphoma. Its phenotype showed pure T-cell type with CD3+, CD56-, and TCR+ accompanied by Epstein-Barr virus infection. Although the lesions were localized in the nasal mucosa and facial skin (stage IE), local irradiation could not achieve complete remission (CR). We then administered 5 courses of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) regimen followed by high-dose chemotherapy with an autologous peripheral blood stem cell transplantation. This therapy resulted in CR. Our results suggest that this lymphoma subtype may be cured by means of intensive treatment soon after diagnosis. [ABSTRACT FROM AUTHOR]

The recent developments in the delivery and design of transcription factors put their therapeutic applications within reach, exemplified by cell replacement, cancer differentiation and T-cell based cancer therapies. The success of such applications depends on the efficacy and precision in the action of transcription factors. The biophysical and genetic characterization of the paradigmatic prokaryotic repressors, LacI and TetR and the designer transcription factors, transcription activator-like effector (TALE) and CRISPR-dCas9 revealed common principles behind their efficacy, which can aid the optimization of transcriptional activators and repressors. Further studies will be required to analyze the linkage between dissociation constants and enzymatic activity, the role of phase separation and squelching in activation and repression and the long-range interaction of transcription factors with epigenetic regulators in the context of the chromosomes. Understanding these mechanisms will help to tailor natural and synthetic transcription factors to the needs of specific applications. [ABSTRACT FROM AUTHOR]

The positive transcription elongation factor b (P-TEFb) was first identified as a general factor that stimulates transcription elongation by RNA polymerase II (RNAPII), but soon afterwards it turned out to be an essential cellular co-factor of human immunodeficiency virus (HIV) transcription mediated by viral Tat proteins. Studies on the mechanisms of Tat-dependent HIV transcription have led to radical advances in our knowledge regarding the mechanism of eukaryotic transcription, including the discoveries that P-TEFb-mediated elongation control of cellular transcription is a main regulatory step of gene expression in eukaryotes, and deregulation of P-TEFb activity plays critical roles in many human diseases and conditions in addition to HIV/AIDS. P-TEFb is now recognized as an attractive and promising therapeutic target for inflammation/autoimmune diseases, cardiac hypertrophy, cancer, infectious diseases, etc. In this review article, I will summarize our knowledge about basic P-TEFb functions, the regulatory mechanism of P-TEFb-dependent transcription, P-TEFb's involvement in biological processes and diseases, and current approaches to manipulating P-TEFb functions for the treatment of these diseases. [ABSTRACT FROM AUTHOR]

Ototoxicity is a major adverse effect of platinum-based chemotherapeutics and currently, there remains a lack of United States Food and Drug Administration-approved therapies to prevent or treat this problem. In our study, we examined the role of the sphingosine 1-phosphate receptor 2 (S1P2) in attenuating cisplatin-induced ototoxicity in several different animal models and cell lines. We found that ototoxicity in S1P2 knockout mice is dependent on reactive oxygen species (ROS) production and that S1P2 receptor activation with a specific agonist, CYM-5478, significantly attenuates cisplatin-induced defects, including hair cell degeneration in zebrafish and prolonged auditory brainstem response latency in rats. We also evaluated the cytoprotective effect of CYM-5478 across different cell lines and showed that CYM-5478 protects neural-derived cell lines but not breast cancer cells against cisplatin toxicity. We show that this selective protection of CYM-5478 is due to its differential effects on key regulators of apoptosis between neural cells and breast cancer cells. Overall, our study suggests that targeting the S1P2 receptor represents a promising therapeutic approach for the treatment of cisplatin-induced ototoxicity in cancer patients. [ABSTRACT FROM AUTHOR]

A heritable polymorphism within regulatory sequences of the LMO1 gene is associated with its elevated expression and increased susceptibility to develop neuroblastoma, but the oncogenic pathways downstream of the LMO1 transcriptional co-regulatory protein are unknown. Our ChIP-seq and RNA-seq analyses reveal that a key gene directly regulated by LMO1 and MYCN is ASCL1, which encodes a basic helix-loop-helix transcription factor. Regulatory elements controlling ASCL1 expression are bound by LMO1, MYCN and the transcription factors GATA3, HAND2, PHOX2B, TBX2 and ISL1—all members of the adrenergic (ADRN) neuroblastoma core regulatory circuitry (CRC). ASCL1 is required for neuroblastoma cell growth and arrest of differentiation. ASCL1 and LMO1 directly regulate the expression of CRC genes, indicating that ASCL1 is a member and LMO1 is a coregulator of the ADRN neuroblastoma CRC. Polymorphisms in LMO1 are associated with increased susceptibility to develop neuroblastoma. Here, the authors show that LMO1 directly induces the transcription factor ASCL1, which regulates the differentiation of neurons, demonstrating that ASCL1 is part of the adrenergic neuroblastoma core regulatory circuit. [ABSTRACT FROM AUTHOR]

Rhabdomyosarcoma (RMS) is a family of soft tissue cancers that are related to the skeletal muscle lineage and predominantly occur in children and young adults. A specific chromosomal translocation t(2;13)(q35;q14) that gives rise to the chimeric oncogenic transcription factor PAX3-FOXO1 has been identified as a hallmark of the aggressive alveolar subtype of RMS. PAX3-FOXO1 cooperates with additional molecular changes to promote oncogenic transformation and tumorigenesis in various human and murine models. Its expression is generally restricted to RMS tumor cells, thus providing a very specific target for therapeutic approaches for these RMS tumors. In this article, we review the recent understanding of PAX3-FOXO1 as a transcription factor in the pathogenesis of this cancer and discuss recent developments to target this oncoprotein for treatment of RMS. [ABSTRACT FROM AUTHOR]

The CCAAT enhancer-binding protein α (C/EBPα) plays an important role in myeloid cell differentiation and in the enhancement of C/EBPα expression/activity, which can lead to granulocytic differentiation in acute myeloid leukemia (AML) cells. We found that styryl quinazolinones induce upregulation of C/EBPα expression, and thereby induce myeloid differentiation in human myeloid leukemia cell lines. We screened a series of active styryl quinazolinones and evaluated the structure–activity relationship (SAR) of these small molecules in inducing C/EBPα expression—thereby prompting the leukemic cells to differentiate. We observed that compound 78 causes differentiation at 3 μM concentration, while 1 induces differentiation at 10 μM concentration. We also observed an increase in the expression of neutrophil differentiation marker CD11b upon treatment with 78. Both the C/EBPα and C/EBPε levels were found to be upregulated by treatment with 78. These SAR findings are inspiration to develop further modified styryl quinazolinones, in the path of this novel differentiation therapy, which can contribute to the care of patients with AML. [ABSTRACT FROM AUTHOR]

Transcription factors are involved in a large number of human diseases such as cancers for which they account for about 20% of all oncogenes identified so far. For long time, with the exception of ligand-inducible nuclear receptors, transcription factors were considered as “undruggable” targets. Advances knowledge of these transcription factors, in terms of structure, function (expression, degradation, interaction with co-factors and other proteins) and the dynamics of their mode of binding to DNA has changed this postulate and paved the way for new therapies targeted against transcription factors. Here, we discuss various ways to target transcription factors in cancer models: by modulating their expression or degradation, by blocking protein/protein interactions, by targeting the transcription factor itself to prevent its DNA binding either through a binding pocket or at the DNA-interacting site, some of these inhibitors being currently used or evaluated for cancer treatment. Such different targeting of transcription factors by small molecules is facilitated by modern chemistry developing a wide variety of original molecules designed to specifically abort transcription factor and by an increased knowledge of their pathological implication through the use of new technologies in order to make it possible to improve therapeutic control of transcription factor oncogenic functions. [ABSTRACT FROM AUTHOR]

Transcription factors are managers of the cellular factory, and key components to many diseases. Many non-coding single nucleotide polymorphisms affect transcription factors, either by directly altering the protein or its functional activity at individual binding sites. Here we first briefly summarize high-throughput approaches to studying transcription factor activity. We then demonstrate, using published chromatin accessibility data (specifically ATAC-seq), that the genome-wide profile of TF recognition motifs relative to regions of open chromatin can determine the key transcription factor altered by a perturbation. Our method of determining which TFs are altered by a perturbation is simple, is quick to implement, and can be used when biological samples are limited. In the future, we envision that this method could be applied to determine which TFs show altered activity in response to a wide variety of drugs and diseases. [ABSTRACT FROM AUTHOR]

The growing number of patients with chronic kidney disease (CKD) is recognized as an emerging problem worldwide. Recent studies have indicated that deregulation of transcription factors is associated with the onset or progression of kidney disease. Several clinical trials indicated that regression of CKD may be feasible via activation of the transcription factor nuclear factor erythroid-2 related factor 2 (Nrf2), which suggests that transcription factors may be potential drug targets for CKD. Agents stabilizing hypoxia-inducible factor (HIF), which may be beneficial for renal anemia and renal protection, are also now under clinical trial. Recently, we have reported that the transcription factor Kruppel-like factor 4 (KLF4) regulates the glomerular podocyte epigenome, and that the antiproteinuric effect of the renin–angiotensin system blockade may be partially mediated by KLF4. KLF4 is one of the Yamanaka factors that induces iPS cells and is reported to be involved in epigenetic remodeling. In this article, we summarize the transcription factors associated with CKD and particularly focus on the possibility of transcription factors being novel drug targets for CKD through epigenetic modulation. [ABSTRACT FROM AUTHOR]

Lysine-specific demethylase 1 (LSD1) mainly removes methyl groups of mono- or di-methylated lysine residues at the fourth position of histone H3 to epigenetically regulate the expression of genes associated with several diseases, such as cancer. Therefore, LSD1 inactivators are expected to be used as therapeutic agents. In this study, to identify novel peptide-based LSD1 inactivators, we focused on the X-ray structure of LSD1 complexed with a H3 peptide-based suicide substrate. It has been proposed that a methylated histone substrate forms three consecutive γ-turn structures in the active pocket of LSD1. Based on this, we designed and synthesized novel histone H3 peptide-based LSD1 inactivators 2a–c by incorporating various α,α-disubstituted amino acids with γ-turn-inducing structures. Among synthetic peptides 2a–c, peptide 2b incorporating two 1-aminocyclohexanecarboxylic acids at both sides of a lysine residue bearing a trans-2-phenylcyclopropylamine (PCPA) moiety, which is a pharmacophore for LSD1 inactivation, was the most potent and selective LSD1 inactivator. These findings are useful for the further development of histone H3 peptide-based LSD1 inactivators. [ABSTRACT FROM AUTHOR]

Cancer cells are highly reliant on certain molecular pathways, which support their survival and proliferation. The fundamental concept of molecularly targeted therapy is to target a protein that is specifically deregulated or overexpressed in cancer cells. However, drug resistance and tumor heterogeneity are major obstacles in the development of specific inhibitors. Additionally, many driver oncogenes exert their oncogenic property via abnormal expression without having genetic mutations. Interestingly, recent accumulating evidence has demonstrated that many critical cancer genes are driven by a unique class of enhancers termed super-enhancers. Genes associated with super-enhancers are relatively more susceptible to the inhibition of general transcriptional machinery compared with genes that are regulated by typical enhancers. Cancer cells are more sensitive to treatment with small-molecule inhibitors of CDK7 or BRD4 than non-transformed cells. These findings proposed a novel strategy to identify functionally important genes as well as novel therapeutic modalities in cancer. This approach would be particularly useful for genetically complicated cancers, such as adult T-cell leukemia (ATL), whereby a large mutational burden is present, but the functional consequences of each mutation have not been well-studied. In this review, we discuss recent findings on super-enhancers, underlying mechanisms, and the efficacy of small-molecule transcriptional inhibitors in ATL. [ABSTRACT FROM AUTHOR]

Aberrant activation of hedgehog (Hh) signaling has been observed in a wide variety of tumors and accounts for more than 25% of human cancer deaths. Inhibitors targeting the Hh signal transducer Smoothened (SMO) are widely used and display a good initial efficacy in patients suffering from basal cell carcinoma (BCC); however, a large number of patients relapse. Though SMO mutations may explain acquired therapy resistance, a growing body of evidence suggests that the non-canonical, SMO-independent activation of the Hh pathway in BCC patients can also account for this adverse effect. In this review, we highlight the importance of glioma-associated oncogene (GLI) transcription factors (the main downstream effectors of the canonical and the non-canonical Hh cascade) and their putative role in the regulation of multiple oncogenic signaling pathways. Moreover, we discuss the contribution of the Hh signaling to malignant transformation and propose GLIs as central hubs in tumor signaling networks and thus attractive molecular targets in anti-cancer therapies. [ABSTRACT FROM AUTHOR]

Transcription is a crucial step in the life cycle of the human immunodeficiency virus type 1 (HIV 1) and is primarily involved in the maintenance of viral latency. Both viral and cellular transcription factors, including transcriptional activators, suppressor proteins and epigenetic factors, are involved in HIV transcription from the proviral DNA integrated within the host cell genome. Among them, the virus-encoded transcriptional activator Tat is the master regulator of HIV transcription. Interestingly, unlike other known transcriptional activators, Tat primarily activates transcriptional elongation and initiation by interacting with the cellular positive transcriptional elongation factor b (P-TEFb). In this review, we describe the molecular mechanism underlying how Tat activates viral transcription through interaction with P-TEFb. We propose a novel therapeutic strategy against HIV replication through blocking Tat action. [ABSTRACT FROM AUTHOR]