Interaction of the oncoprotein transcription factor MYC with its chromatin cofactor WDR5 is essential for tumor maintenance

The oncoprotein transcription factor MYC is overexpressed in the majority of cancers. Key to its oncogenic activity is the ability of MYC to regulate gene expression patterns that drive and maintain the malignant state. MYC is also considered a validated anticancer target, but efforts to pharmacologically inhibit MYC have failed. The dependence of MYC on cofactors creates opportunities for therapeutic intervention, but for any cofactor this requires structural understanding of how the cofactor interacts with MYC, knowledge of the role it plays in MYC function, and demonstration that disrupting the cofactor interaction will cause existing cancers to regress. One cofactor for which structural information is available is WDR5, which interacts with MYC to facilitate its recruitment to chromatin. To explore whether disruption of the MYC–WDR5 interaction could potentially become a viable anticancer strategy, we developed a Burkitt's lymphoma system that allows replacement of wild-type MYC for mutants that are defective for WDR5 binding or all known nuclear MYC functions. Using this system, we show that WDR5 recruits MYC to chromatin to control the expression of genes linked to biomass accumulation. We further show that disrupting the MYC–WDR5 interaction within the context of an existing cancer promotes rapid and comprehensive tumor regression in vivo. These observations connect WDR5 to a core tumorigenic function of MYC and establish that, if a therapeutic window can be established, MYC–WDR5 inhibitors could be developed as anticancer agents.

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Aptamers against mouse and human tumor-infiltrating myeloid cells as reagents for targeted chemotherapy

Science Translational Medicine ◽

10.1126/scitranslmed.aav9760 ◽

2020 ◽

Vol 12 (548) ◽

pp. eaav9760

Author(s):

Adriana De La Fuente ◽

Serena Zilio ◽

Jimmy Caroli ◽

Dimitri Van Simaeys ◽

Emilia M. C. Mazza ◽

...

Keyword(s):

Mouse Models ◽

Anticancer Agents ◽

Targeted Delivery ◽

Tumor Regression ◽

Ex Vivo ◽

Myeloid Cells ◽

Human Tumor ◽

Rna Aptamers ◽

Targeted Chemotherapy

Local delivery of anticancer agents has the potential to maximize treatment efficacy and minimize the acute and long-term systemic toxicities. Here, we used unsupervised systematic evolution of ligands by exponential enrichment to identify four RNA aptamers that specifically recognized mouse and human myeloid cells infiltrating tumors but not their peripheral or circulating counterparts in multiple mouse models and from patients with head and neck squamous cell carcinoma (HNSCC). The use of these aptamers conjugated to doxorubicin enhanced the accumulation and bystander release of the chemotherapeutic drug in both primary and metastatic tumor sites in breast and fibrosarcoma mouse models. In the 4T1 mammary carcinoma model, these doxorubicin-conjugated aptamers outperformed Doxil, the first clinically approved highly optimized nanoparticle for targeted chemotherapy, promoting tumor regression after just three administrations with no detected changes in weight loss or blood chemistry. These RNA aptamers recognized tumor infiltrating myeloid cells in a variety of mouse tumors in vivo and from human HNSCC ex vivo. This work suggests the use of RNA aptamers for the detection of myeloid-derived suppressor cells in humans and for a targeted delivery of chemotherapy to the tumor microenvironment in multiple malignancies.

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Transcriptome Analysis Reveals the Different Response to Toxic Stress in Rootstock Grafted and Non-Grafted Cucumber Seedlings

International Journal of Molecular Sciences ◽

10.3390/ijms21030774 ◽

2020 ◽

Vol 21 (3) ◽

pp. 774

Author(s):

Xuemei Xiao ◽

Jian Lv ◽

Jianming Xie ◽

Zhi Feng ◽

Ning Ma ◽

...

Keyword(s):

Transcription Factor ◽

Nitrogen Metabolism ◽

Expression Patterns ◽

Calvin Cycle ◽

Biomass Accumulation ◽

Tca Cycle ◽

Mapk Signaling ◽

Carbon And Nitrogen ◽

Related Transcription Factor ◽

Carbon And Nitrogen Metabolism

Autotoxicity of root exudates is one of the main reasons for consecutive monoculture problem (CMP) in cucumber under greenhouse cultivation. Rootstock grafting may improve the tolerance of cucumber plants to autotoxic stress. To verify the enhanced tolerance to autotoxic stress and illuminate relevant molecular mechanism, a transcriptomic comparative analysis was performed between rootstock grafted (RG) and non-grafted (NG) cucumber plants by a simulation of exogenous cinnamic acid (CA). The present study confirmed that relatively stable plant growth, biomass accumulation, chlorophyll content, and photosynthesis was observed in RG than NG under CA stress. We identified 3647 and 2691 differentially expressed genes (DEGs) in NG and RG cucumber plants when compared to respective control, and gene expression patterns of RNA-seq was confirmed by qRT-PCR. Functional annotations revealed that DEGs response to CA stress were enriched in pathways of plant hormone signal transduction, MAPK signaling pathway, phenylalanine metabolism, and plant-pathogen interaction. Interestingly, the significantly enriched pathway of photosynthesis-related, carbon and nitrogen metabolism only identified in NG, and most of DEGs were down-regulated. However, most of photosynthesis, Calvin cycle, glycolysis, TCA cycle, and nitrogen metabolism-related DEGs exhibited not or slightly down-regulated in RG. In addition, several stress-related transcription factor families of AP2/ERF, bHLH, bZIP, MYB. and NAC were uniquely triggered in the grafted cucumbers. Overall, the results of this study suggest that rootstock grafting improve the tolerance of cucumber plants to autotoxic stress by mediating down-regulation of photosynthesis, carbon, and nitrogen metabolism-related DEGs and activating the function of stress-related transcription factor. The transcriptome dataset provides an extensive sequence resource for further studies of autotoxic mechanism at molecular level.

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Androgen-Induced Rhox Homeobox Genes Modulate the Expression of AR-Regulated Genes

Molecular Endocrinology ◽

10.1210/me.2009-0303 ◽

2010 ◽

Vol 24 (1) ◽

pp. 60-75 ◽

Cited By ~ 31

Author(s):

Zhiying Hu ◽

Dineshkumar Dandekar ◽

Peter J. O'Shaughnessy ◽

Karel De Gendt ◽

Guido Verhoeven ◽

...

Keyword(s):

Transcription Factor ◽

Sertoli Cells ◽

Cell Cycle Regulation ◽

Expression Patterns ◽

Expression Vectors ◽

Founding Member ◽

Cell Clones ◽

Cycle Regulation ◽

Lines Of Evidence

Abstract Rhox5, the founding member of the reproductive homeobox on the X chromosome (Rhox) gene cluster, encodes a homeodomain-containing transcription factor that is selectively expressed in Sertoli cells, where it promotes the survival of male germ cells. To identify Rhox5-regulated genes, we generated 15P-1 Sertoli cell clones expressing physiological levels of Rhox5 from a stably transfected expression vector. Microarray analysis identified many genes altered in expression in response to Rhox5, including those encoding proteins controlling cell cycle regulation, apoptosis, metabolism, and cell-cell interactions. Fifteen of these Rhox5-regulated genes were chosen for further analysis. Analysis of Rhox5-null male mice indicated that at least nine of these are Rhox5-regulated in the testes in vivo. Many of them have distinct postnatal expression patterns and are regulated by Rhox5 at different postnatal time points. Most of them are expressed in Sertoli cells, indicating that they are candidates to be directly regulated by Rhox5. Transfection analysis with expression vectors encoding different mouse and human Rhox family members revealed that the regulatory response of a subset of these Rhox5-regulated genes is both conserved and redundant. Given that Rhox5 depends on androgen receptor (AR) for expression in Sertoli cells, we examined whether some Rhox5-regulated genes are also regulated by AR. We provide several lines of evidence that this is the case, leading us to propose that RHOX5 serves as a key intermediate transcription factor that directs some of the actions of AR in the testes.

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Structure and functional implications of WYL-domain-containing transcription factor PafBC involved in the mycobacterial DNA damage response

10.1101/612655 ◽

2019 ◽

Author(s):

Andreas U. Müller ◽

Marc Leibundgut ◽

Nenad Ban ◽

Eilika Weber-Ban

Keyword(s):

Dna Damage ◽

Transcription Factor ◽

Transcription Factors ◽

Rna Binding ◽

Rna Binding Proteins ◽

Structural Information ◽

Rna Molecules ◽

Bacterial Transcription ◽

Arthrobacter Aurescens

AbstractIn mycobacteria, transcriptional activator PafBC is responsible for upregulating the majority of genes induced by DNA damage. Understanding the mechanism of PafBC activation is impeded by a lack of structural information on this transcription factor that contains a widespread, but poorly understood WYL domain frequently encountered in bacterial transcription factors. Here, we determined the crystal structure ofArthrobacter aurescensPafBC. The protein consists of two modules, each harboring an N-terminal helix-turn-helix DNA binding domain followed by a central WYL and a C-terminal extension (WCX) domain. The WYL domains exhibit Sm-folds, while the WCX domains adopt ferredoxin-like folds, both characteristic for RNA binding proteins. Our results suggest a mechanism of regulation in which WYL domain-containing transcription factors may be activated by binding RNA molecules. Using anin vivomutational screen inMycobacterium smegmatis, we identify potential co-activator binding sites on PafBC.

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Maturation stage–specific regulation of megakaryopoiesis by pointed-domain Ets proteins

Blood ◽

10.1182/blood-2006-04-019760 ◽

2006 ◽

Vol 108 (7) ◽

pp. 2198-2206 ◽

Cited By ~ 52

Author(s):

Liyan Pang ◽

Hai-Hui Xue ◽

Gabor Szalai ◽

Xun Wang ◽

Yuhuan Wang ◽

...

Keyword(s):

Transcription Factor ◽

Fetal Liver ◽

Maturation Stage ◽

Platelet Factor ◽

Ets Proteins ◽

Expression Of Genes ◽

Friend Leukemia ◽

Specific Regulation

Abstract Numerous megakaryocyte-specific genes contain signature Ets-binding sites in their regulatory regions. Fli-1 (friend leukemia integration 1), an Ets transcription factor, is required for the normal maturation of megakaryocytes and controls the expression of multiple megakaryocyte-specific genes. However, in Fli-1–/– mice, early megakaryopoiesis persists, and the expression of the early megakaryocyte-specific genes, αIIb and cMpl, is maintained, consistent with functional compensation by a related Ets factor(s). Here we identify the Ets protein GABPα (GA-binding protein α) as a regulator of early megakaryocyte-specific genes. Notably, GABPα preferentially occupies Ets elements of early megakaryocyte-specific genes in vitro and in vivo, whereas Fli-1 binds both early and late megakaryocyte-specific genes. Moreover, the ratio of GABPα/Fli-1 expression declines throughout megakaryocyte maturation. Consistent with this expression pattern, primary fetal liver–derived megakaryocytes from Fli-1–deficient murine embryos exhibit reduced expression of genes associated with late stages of maturation (glycoprotein [GP] Ibα, GPIX, and platelet factor 4 [PF4]), whereas GABPα-deficient megakaryocytes were mostly impaired in the expression of early megakaryocyte-specific genes (αIIb and cMpl). Finally, mechanistic experiments revealed that GABPα, like Fli-1, can impart transcriptional synergy between the hematopoietic transcription factor GATA-1 and its cofactor FOG-1 (friend of GATA-1). In concert, these data reveal disparate, but overlapping, functions of Ets transcription factors at distinct stages of megakaryocyte maturation.

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An in vivo screen of noncoding loci reveals that Daedalus is a gatekeeper of an Ikaros-dependent checkpoint during haematopoiesis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1918062118 ◽

2021 ◽

Vol 118 (3) ◽

pp. e1918062118

Author(s):

Christian C. D. Harman ◽

Will Bailis ◽

Jun Zhao ◽

Louisa Hill ◽

Rihao Qu ◽

...

Keyword(s):

Transcription Factor ◽

Expression Patterns ◽

Adaptive Immune System ◽

Dna Interaction ◽

Lineage Commitment ◽

Lymphoid Lineage ◽

Severe Reduction ◽

Specific Manner ◽

In Vivo Screen

Haematopoiesis relies on tightly controlled gene expression patterns as development proceeds through a series of progenitors. While the regulation of hematopoietic development has been well studied, the role of noncoding elements in this critical process is a developing field. In particular, the discovery of new regulators of lymphopoiesis could have important implications for our understanding of the adaptive immune system and disease. Here we elucidate how a noncoding element is capable of regulating a broadly expressed transcription factor, Ikaros, in a lymphoid lineage-specific manner, such that it imbues Ikaros with the ability to specify the lymphoid lineage over alternate fates. Deletion of the Daedalus locus, which is proximal to Ikaros, led to a severe reduction in early lymphoid progenitors, exerting control over the earliest fate decisions during lymphoid lineage commitment. Daedalus locus deletion led to alterations in Ikaros isoform expression and a significant reduction in Ikaros protein. The Daedalus locus may function through direct DNA interaction as Hi-C analysis demonstrated an interaction between the two loci. Finally, we identify an Ikaros-regulated erythroid-lymphoid checkpoint that is governed by Daedalus in a lymphoid-lineage–specific manner. Daedalus appears to act as a gatekeeper of Ikaros’s broad lineage-specifying functions, selectively stabilizing Ikaros activity in the lymphoid lineage and permitting diversion to the erythroid fate in its absence. These findings represent a key illustration of how a transcription factor with broad lineage expression must work in concert with noncoding elements to orchestrate hematopoietic lineage commitment.

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279.Infertility in mice with null mutation of the Egr-1 transcription factor

Reproduction Fertility and Development ◽

10.1071/srb04abs279 ◽

2004 ◽

Vol 16 (9) ◽

pp. 279 ◽

Cited By ~ 1

Author(s):

D. L. Russell

Keyword(s):

Transcription Factor ◽

Target Genes ◽

Ovarian Function ◽

Ovarian Follicle ◽

Follicular Development ◽

Prostaglandin E ◽

Lh Receptor ◽

Expression Of Genes

Female infertility has been reported in two lines of mice with mutation of the Egr-1 gene. One underlying cause of this defect is deficient LH production by pituitary gonadotropes. However, Egr-1 is also acutely regulated by both FSH and LH in ovarian granulosa cells (1). A role for this transcription factor in regulating gonadotrophin responsive target genes and ovarian function is hypothesised. Indeed the LH-receptor is a proposed target of Egr-1 regulation, but this has not been investigated in detail in vivo and is difficult to reconcile with the pattern of Egr-1 expression. In this study, the role of Egr-1 within the ovarian follicle was investigated using exogenous gonadotropin replacement in Egr-1–/– mice . Adult Egr-1–/– female mice superovulated by sequential PMSG and hCG stimulation and mated with proven male breeders failed to produced offspring while 90% of heterozygous females got pregnant and produced litters (7.4 � 2.9 pups per litter) within 22 days of stimulation. Recovery of oocytes from oviducts of immature superovulated mice revealed a reduced ovulation rate in null females (6.3 � 3.8 oocytes) compared to their heterozygous (18.0 � 6.5) and WT (17.8 � 6.8) littermates. Gross morphology and histology of exogenously stimulated ovaries were indistinguishable from their heterozygous or WT counterparts. Surprisingly, no alteration was detectable in the mRNA expression of previously reported direct Egr-1 responsive genes, namely LH-receptor and membrane prostaglandin E synthase (mPGES). Nor were mRNA for two critical ovulatory genes with putative Egr-1 response elements, ADAMTS-1 or versican V1 altered. Temporal and spatial expression of genes involved in ovarian steroidogenesis, P450scc and Cyp17 and LH-receptor, were indistinguishable from normal littermates during exogenously controled follicular development. Combined observations of acute Egr-1 induction by gonadotropins, reduced ovulation and complete infertility suggest an important role for Egr-1 in ovarian function. However, genes identified as targets of Egr-1 regulation in other studies proved to be Egr-1 independent in this model. (1) Russell et al. (2003) Mol. Endo. 17, 520.

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Selective Inhibition of the Leukemia Fusion Protein CBFβ-SMMHC By Small Molecule AI-10-49 in the Treatment of Inv(16) AML

Blood ◽

10.1182/blood.v124.21.390.390 ◽

2014 ◽

Vol 124 (21) ◽

pp. 390-390 ◽

Cited By ~ 1

Author(s):

John Anto Pulikkan ◽

Anuradha Illendula ◽

Jolanta Grembecka ◽

Liting Xue ◽

Roger Rajewski ◽

...

Keyword(s):

Transcription Factor ◽

Fusion Protein ◽

Small Molecule ◽

Conflicts Of Interest ◽

Normal Karyotype ◽

Therapeutic Window ◽

Rank Test ◽

Term Survival ◽

Normal Human

Abstract The leukemia fusion protein CBFβ-SMMHC, associated with acute myeloid leukemia (AML) with chromosome inversion inv(16)(p13q22), is a driver mutation in leukemia development. Studies by our laboratory and others have established that CBFβ-SMMHC outcompetes CBFβ for binding to RUNX1, deregulates RUNX1 transcription factor activity in hematopoiesis, and induces AML. Studies in mice and patient AML cells support the concept that CBFβ-SMMHC generates pre-leukemic myeloid progenitors, which acquire cooperating mutations to progress to leukemia. Current inv(16) AML treatment using non-selective cytotoxic chemotherapy results in a good initial response, but long-term survival is approximately 60%. This suggests that additional efforts are necessary for the development of improved therapeutic response for CBF AML patients. We have identified AI-4-57 as the active compound that inhibits CBFβ-SMMHC/RUNX1 binding (IC50= 22 uM), using a screen of the NCI diversity set library. AI-4-57 specifically binds to the CBFβ portion of CBFβ-SMMHC, as determined by NMR. This compound was modified in order to improve its potency and stability, and identified the divalent derivative AI-10-49 for further characterization. AI-10-49 showed increased potency (IC50= 0.26 µM) improved in vivo pharmacokinetics (serum t1/2 = 380 min), and enhanced activity in inv(16) positive ME-1 cells (IC50 = 0.6 uM). Importantly, AI-10-49 showed negligible activity (IC50>25 μM) in normal human bone marrow, defining a robust potential therapeutic window. Co-immunoprecipitation assays of ME-1 cells demonstrated that AI-10-49 (1µM for six hours) effectively and specifically dissociated RUNX1/CBFβ-SMMHC when compared to CBFβ/RUNX1 binding (Meandiss: 90% and 15%, respectively). Expression of RUNX1 target genes RUNX3, CSF1R, and CEBPA is repressed by CBFβ-SMMHC in inv(16) AML. The occupancy of RUNX1 in their promoters was significantly increased by chromatin-immunoprecipitation (8, 2.2, and 8 fold, respectively) in 6 hour treated (1µM AI-10-49) ME-1 cells, suggesting that CBFβ-SMMHC represses RUNX1 targets by blocking RUNX1 binding to target regulatory sites. In addition, RUNX3, CSF1R, and CEBPA expression increased 2 to 8 fold when compared to DMSO treated ME-1 cells. Importantly, RUNX1 occupancy and target expression changes were not observed in inv(16)-negative U937 cells. These data establish AI-10-49 selectivity in inhibiting CBFβ-SMMHC binding to RUNX1 and validate our approach of using bivalent inhibitors to achieve this specificity. To test AI-10-49 activity in vivo, mice were transplanted with leukemic cells expressing CBFβ-SMMHC and NrasG12D (from Cbfb+/MYH11:Ras+/G12Dknock-in mice), and treated, starting at day five post transplantation, with vehicle (DMSO) or 200 mg/kg AI-10-49 for ten days. The median latency of leukemia was delayed one fold in AI-10-49 treated mice (MLAI-10-49= 61 days, MLDMSO= 33.5 days, P=2.7x10-6; Log-rank test). In addition, toxicity assays revealed no detectable cumulative toxicity in mice treated with AI-10-49 for seven days. To test the efficacy of AI-10-49 in human inv(16) AML, the survival of four inv(16) and four normal karyotype AML patient samples were tested in 48 hour dose response assays. The viability of inv(16) patient cells was clearly reduced by AI-10-49 (viability: 50%, 10 μM AI-10-49/DMSO). In contrast, the viability of normal karyotype AML samples was unaffected at concentrations below 20µM. These studies show that AI-10-49 selectively inhibits viability in inv(16) AML blasts, while having negligible effects on AML blasts with normal karyotype or on normal human hematopoietic progenitors. Dysregulated gene expression is a hallmark of cancer and is particularly important for the maintenance of cancer stem cells, such as self-renewal, leading to relapse. The targeting of proteins that drive transcriptional dysregulation, so called “transcription therapy”, represents an avenue for drug development with immense potential. This study reports the development of a small molecule with high efficacy and specific in the inhibition of CBFβ-SMMHC activity while having a minimal effect on CBFβ function. In summary, AI-10-49 is a potent first generation CBFβ-SMMHC inhibitor that induces cell death in inv(16) AML cells and establishes a proof-of-principle that transcription factor fusion oncoproteins can be directly targeted for leukemia treatment. Disclosures No relevant conflicts of interest to declare.

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Characterization of POU2F1 Gene and Its Potential Impact on the Expression of Genes Involved in Fur Color Formation in Rex Rabbit

Genes ◽

10.3390/genes11050575 ◽

2020 ◽

Vol 11 (5) ◽

pp. 575 ◽

Cited By ~ 1

Author(s):

Naisu Yang ◽

Bohao Zhao ◽

Shuaishuai Hu ◽

Zhiyuan Bao ◽

Ming Liu ◽

...

Keyword(s):

Transcription Factor ◽

Expression Patterns ◽

Dorsal Skin ◽

Color Formation ◽

Expression Of Genes ◽

Potential Impact ◽

Fur Color ◽

Rex Rabbit

The naturally colorful fur of the Rex rabbit is becoming increasingly popular in the modern textile market. Our previous study found that POU class 2 homeobox 1 gene (POU2F1) potentially affects the expression of genes involved in fur color formation in the Rex rabbit, but the function and regulation of POU2F1 has not been reported. In this study, the expression patterns of POU2F1 in Rex rabbits of various colors, as well as in different organs, were analyzed by RT-qPCR. Interference and overexpression of POU2F1 were used to identify the potential effects of POU2F1 on other genes related to fur color formation. The results show that the levels of POU2F1 expression were significantly higher in the dorsal skin of the brown and protein yellow Rex rabbits, compared with that of the black one. POU2F1 mRNAs were widespread in the tissues examined in this study and showed the highest level in the lungs. By transfecting rabbit melanocytes with an POU2F1-overexpression plasmid, we found that the POU2F1 protein was located at the nucleus, and the protein showed the classic characteristics of a transcription factor. In addition, abnormal expression of POU2F1 significantly affected the expression of pigmentation-related genes, including SLC7A11, MITF, SLC24A5, MC1R, and ASIP, revealing the regulatory roles of POU2F1 on pigmentation. The results provide the basis for further exploration of the role of POU2F1 in fur color formation of the Rex rabbit.

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Disrupting Ectopic Super-Enhancers to Treat Multiple Myeloma

Blood ◽

10.1182/blood-2021-147551 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1593-1593

Author(s):

Seth Welsh ◽

Daniel Riggs ◽

Erin Meermeier ◽

Chang-Xin Shi ◽

Victoria Garbitt ◽

...

Keyword(s):

Multiple Myeloma ◽

Transcription Factor ◽

Mouse Model ◽

Therapeutic Response ◽

Genetically Engineered ◽

Therapeutic Window ◽

Super Enhancer ◽

Genetically Engineered Mouse Model

Abstract Multiple myeloma (MM) is an incurable form of plasma cell cancer in which primary and secondary chromosomal translocations routinely juxtapose oncogenes to plasma cell-specific super-enhancers. Coincidentally, drugs which target super-enhancers have had success clinically. For example, immunomodulatory imide drugs (IMiDs) degrade super-enhancer-binding pioneer factors IKAROS and AIOLOS, while glucocorticoids (Dexamethasone) and proteasome inhibitors (Bortezomib) have the ability to transrepress or block the processing of super-enhancer-forming NF-κB proteins, respectively. Currently, alternative enhancer-targeting drugs are also in clinical development, like p300 inhibitors which target the acetyl-binding bromodomains and/or histone acetyl transferase activity of the chromatin-regulating coactivator homologs CBP and EP300. Despite showing therapeutic promise, our understanding of how these drugs function, alone or together, remains incomplete. Case in point, we find that IMiD-induced degradation of its target proteins IKAROS and AIOLOS does not guarantee a therapeutic response in vitro, and patients successfully treated with IMiDs eventually relapse; meanwhile, coactivator-targeting therapies like p300 inhibitors are often too toxic in vivo, and lack a therapeutic window. To improve the outcomes of MM patients we need to understand the heterogeneous genetics and transcription-factor milieus of the myeloma enhancer landscape, as well as how to increase the precision of enhancer-disrupting drugs. To accomplish this, our lab utilizes more than 60 human myeloma cell lines that have been extensively characterized at the genetic, proteomic, and drug-therapeutic-response levels. Additionally, we have generated a highly-predictive immunocompetent mouse model (Vk*MYC hCRBN+) that develops human-like MM and is sensitive to both IMiDs and a new class of therapeutics termed "degronimids" (normal mice do not respond to IMiDs or degronimids). Our central hypothesis is that combining a broad coactivator-targeting drug (e.g., the p300 inhibitor GNE-781), with a MM-specific transcription factor-targeting drug (e.g., IMiDs) restricts toxicities to myeloma cells and thus improves the therapeutic window. Currently, we are testing a variety of coactivator-targeting compounds alongside traditional IMiD therapies and other preclinical transcription factor-targeting drugs both in vivo and in vitro. We show that Vk*MYC hCRBN+ mice are exquisitely sensitive to GNE-781, requiring one fourth of the dose needed to treat other cancers and therefore avoiding the neutropenia and thrombocytopenia seen at higher doses. Second, we show that although IMiDs and GNE-781 induce an effective but transient response in vivo as single agents, the combination of the two drugs proved curative, with a progressive deepening of the anti-tumor response occurring even after therapy is discontinued. Ongoing experiments aim to determine how this drug combination, and other coactivator + transcription factor-targeting combinations, permanently disrupt myeloma-specific super-enhancers. Disclosures Neri: BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Bahlis: Sanofi: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genentech: Consultancy. Boise: AstraZeneca: Honoraria, Research Funding; AbbVie/Genentech: Membership on an entity's Board of Directors or advisory committees. Chesi: Abcuro: Patents & Royalties: Genetically engineered mouse model of myeloma; Pi Therapeutics: Patents & Royalties: Genetically engineered mouse model of myeloma; Pfizer: Consultancy; Novartis: Consultancy, Patents & Royalties: human CRBN transgenic mouse; Palleon Pharmaceuticals: Patents & Royalties: Genetically engineered mouse model of myeloma.

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