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  • 1
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    Online Resource
    NFkB p50 (Nfkb1) Contributes to Disease in the Eu-TCL1 Mouse Model of Chronic Lymphocytic Leukemia
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 1248-1248
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 1248-1248
    Abstract: Chronic lymphocytic leukemia (CLL) is a disease of mature B-cells that are resistant to apoptosis and accumulate in the blood over time. Due to the slowly progressing nature of this disease, studies to determine the molecular events leading to defective apoptosis are challenging. Our group has previously reported that during disease progression in the Eμ-TCL1 CLL mouse model, genes become silenced in a progressive manner over the course of the disease. This silencing is due in part to a high degree of methylation at the promoters of key tumor suppressors. However, even though a high degree of methylation is observed in both this mouse model and in CLL patient samples, agents targeting methylation such as decitabine have proven ineffective in CLL therapy. Therefore other novel methods to reverse gene silencing in CLL are an attractive therapeutic option. In our previous study, we observed early transcriptional mechanisms of gene silencing (occurring prior to methylation) involving NF-κB p50 homodimers. NF-κB is a family of transcription factors which is known to play an important role in the progression of CLL. Advances in next generation sequencing have recently identified loss of function mutations in NFKBIE,a negative regulator of NF-κB signaling,in CLL. These mutations contribute to increased nuclear localization (and hence increased activation) of NF-κB subunits. In addition, a mutagenesis screen in the Eμ-TCL1 mouse found that several of the most frequently occurring mutations that contribute to disease progression occur in genes related to the NF-κB family, particularly in the p50 (Nfkb1) gene. In the present study, we have generated a new mouse model to further study the role of p50 in CLL pathogenesis. The Eμ-TCL1 mouse was crossed to the p50-/- mouse. The p50-/- mice are fertile with normal growth and development under sterile conditions; however they do exhibit a defective response to infection and decreased antibody production. As such, animals in this study are housed under pathogen free conditions. The initial cross resulted in mice that were all heterozygous for p50 (p50+/-), and either positive or negative for the TCL1 transgene. The p50+/-; TCL1+ animals were subsequently crossed with one another to generate three genotypes: p50+/+. p50+/- and p50-/-. Animals are monitored for disease by monthly flow cytometry analysis of CD19 and CD5 in whole blood, and leukemia is defined as 〉 10% double positive cells. The p50-/- mice have a significantly lower incidence of leukemia compared to p50+/+ mice (Chi-square p 〈 0.001), and p50+/- mice show an intermediate phenotype (p=0.024 compared to p50-/- mice). Despite pathogen free conditions, some mice within the p50-/- group die at an early age with no evidence of disease. Therefore, competing risks regression was performed to take into account the mice that die without leukemia via the CIF (cumulative incidence function) based on the Fine and Gray model. Differences in time to leukemia between the p50+/+ and p50-/- mice remained significant (Subdistribution Hazard Ratio; SHR = 8.45; 95% CI: 1.86 - 38.47; p=0.006). The p50+/- mice still exhibit an intermediate phenotype, with more separation between the p50+/- and p50-/- (SHR = 4.39; 95% CI: 1.00 - 19.29; p=0.050) than the p50+/- and p50+/+ groups (SHR = 0.52; 95% CI: 0.26 - 1.06; p=0.069). Finally, spleens from p50-/- mice are notably smaller than the p50+/+ littermates (average spleen score of 0-1 for p50-/- versus 2-3 for p50+/+, using a 0-4 scale), indicating that disease in the secondary lymphoid tissues is also affected by the loss of p50 in this model. In conclusion, these data genetically demonstrate the significant contribution of the p50 (Nfkb1) gene to disease progression in the Eµ-TCL1 mouse model. These studies highlight the importance of the NF-κB family in CLL, and suggest that p50 is a promising therapeutic target in this disease. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.1248.1248
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 2
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    Next Generation XPO1 Inhibitor Shows Improved Efficacy and In Vivo Tolerability in Hematologic Malignancies
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 317-317
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 317-317
    Abstract: Restoring nuclear localization of tumor suppressors by blocking exportin 1 (XPO1) holds promise as a new therapeutic paradigm in many cancers, including chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). Oral selective inhibitor of nuclear export (SINE) compounds that covalently modify XPO1 were recently discovered and are exciting new compounds to implement this strategy. Selinexor, the clinical lead SINE, has made progress in Phase I/II clinical trials and is generally well tolerated, but limited to twice weekly dosing, with supportive care. The discovery of novel SINE compounds with improved tolerability is therefore of considerable clinical interest and represents a significant contribution beyond the targeted therapies currently available for hematologic malignancies and a variety of other cancers where upregulation of XPO1 is observed. Presented herein is the discovery of KPT-8602, the next generation SINE compound that shows lower brain penetration, improved tolerability allowing continuous dosing, and improved efficacy beyond any current XPO1 inhibitor. Results: Our crystallography data revealed that KPT-8602 binds covalently to XPO1 through a Michael acceptor that is activated by an electron withdrawing pyrimidyl moiety, allowing a 2-fold increased reversible interaction with XPO1 compared to earlier SINE compounds. The crystal structure of the KPT-8602-XPO1 complex showed interactions between XPO1 and the activating pyrimidyl group. In vitro pull-downs using immobilized GST-nuclear export sequences and purified recombinant XPO1 demonstrated greater reversible binding of KPT-8602 compared to KPT-330 (selinexor). In vivo toxicology studies demonstrated that KPT-8602 possesses lower brain penetration compared to KPT-330 allowing for continuous dosing and improved tolerability. Our results also showed that KPT-8602 induced a comparable level of cytotoxicity as well as inhibition of cell proliferation compared to KPT-330 in primary CLL tumors and in a representative panel of DLBCL cell lines. Furthermore, KPT-8602 inhibited proliferation and induced apoptosis in AML cell lines and primary AML blasts while inducing nuclear accumulation of p53 and NPM1. We hypothesized that these improved pharmacological parameters would allow daily KPT-8602 to abrogate disease progression in CLL and AML animal models. The Eµ-TCL1-C57BL/6 transplant model of CLL was used to evaluate the therapeutic benefit of continuous dosing of KPT-8602. Eµ-TCL1-engrafted mice were treated with KPT-8602 given daily or 2x/week. The KPT-8602 daily cohort had significantly improved survival with a median overall survival of 70 vs 50 days (vs vehicle 33 days), compared to those treated only 2x/week with KPT-8602 (p=0.001). Mice treated with KPT-330 2x/week showed a similar survival to mice treated with KPT-8602 2x/week. Mice given daily KPT-8602 had significantly smaller spleens and reduced circulating leukemic cells compared to all the other groups (p 〈 0.001 for all comparisons). We recently showed the combination of KPT-330 and ibrutinib (bruton tyrosine kinase inhibitor) increases survival compared to ibrutinib alone in Eµ-TCL1-engrafted mice. We therefore tested the effect of KPT-330+ibrutinib or KPT-8602+ibrutinib in a cohort of Eµ-TCL1-engrafted mice compared to any agent alone. Notably, the combination of KPT-8602 to ibrutinib was able to further improve the survival induced by KPT-330+ibrutinib (p=0.008). We next assessed the activity of KPT-8602 in a human leukemia xenograft model of AML where NOD/SCID γ mice were inoculated with MV4-11 cells obtained from spleens of primary MV4-11 xenografts. Recipient mice given KPT-8602 5x/week showed strikingly better outcomes with a median survival of 58 vs 35 days compared to KPT-8602 2x/week (p 〈 0.0001) and KPT-330 2x/week (p 〈 0.0001). Conclusion: Consistent with the in vitro finding of a two-fold enhanced reversibility of XPO1-KPT-8602 binding and lower brain penetration, our data indicate that KPT-8602 allows a prolonged frequent dosing schedule, which leads to an excellent therapeutic benefit and less toxicity in animal models of CLL and AML. These data suggest that KPT-8602 represents a new treatment paradigm and warrants further evaluation in clinical trials of patients with hematologic malignancies, particularly in combination with ibrutinib or other second generation Btk inhibitors. Disclosures Baloglu: Karyopharm Therapeutics Inc.: Employment, Equity Ownership. Shacham:Karyopharm: Employment, Equity Ownership. Kauffman:Karyopharm: Employment, Equity Ownership. Byrd:Acerta Pharma BV: Research Funding. Chook:Karyopharm Therapeutics Inc.: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.317.317
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
    detail.hit.zdb_id: 1468538-3
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  • 3
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    Early Fludarabine Treatment of TCL-1 Transgenic Mice Promotes Drug Resistance through a Mechanism Not Involving p53 Mutations: Implications for Patients with Chronic Lymphocytic Leukemia (CLL).
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 3095-3095
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 3095-3095
    Abstract: Initial therapy for Chronic Lymphocytic Leukemia (CLL) typically includes nucleoside analogs such as fludarabine. Mutations of p53 are uncommon in CLL patients at diagnosis, but are found at increased frequency in patients with prior treatment and are often associated with resistance to standard therapies including fludarabine. The causality of fludarabine treatment to p53 mutation has not been clearly defined. In previous work with the TCL-1 model of CLL, we demonstrated that mice with active leukemia do not have p53 mutations and respond to fludarabine therapy with a modest survival advantage (Johnson et al, Blood108:1334, 2006). We therefore initiated a randomized trial of fludarabine treatment (34mg/kg daily intraperitoneal injection for five days every 28 days) versus observation (treatment with volume-matched vehicle controls on the same dosing schedule) in TCL-1 transgenic mice prior to the onset of leukemia. The goals of this study were to determine if early treatment with fludarabine would 1) delay disease onset; 2) eventually yield a fludarabine-resistant phenotype; or 3) promote development of p53 mutations in mice developing progressive leukemia. Transgenic TCL-1 mice between the ages of eight and 12 weeks were continually treated with fludarabine (n=32) or saline (n=45) until death while being screened monthly for disease progression through changes in WBC count by peripheral blood differentiation smear, lymphocyte subsets by flow cytometry, and nodal and spleen exams. Despite continued treatment with fludarabine, drug resistance as manifested by leukemia and eventual death occurred. Median time to leukemia onset was 308 days (95% CI: 224, ∞) in the fludarabine group and 338 days (95% CI: 252, ∞) in the saline group. Thus, the risk of developing leukemia was not significantly different between the two groups. Of interest, p53 mutations in exons 2–11 were not found in either group (n=10 each) at the time of death. Microarray studies are currently underway to discover other genes differentially expressed between treated and untreated mice that might contribute to fludarabine resistance and will be presented. In conclusion, our data demonstrate that early fludarabine treatment in the TCL-1 transgenic model of CLL does not prevent onset of leukemia, but instead results in disease resistant to fludarabine. The source of fludarabine resistance in this mouse model was not through acquisition of p53 mutations, but rather an alternative unidentified mechanism(s).
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.3095.3095
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
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  • 4
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    Online Resource
    The novel plant-derived agent silvestrol has B-cell selective activity in chronic lymphocytic leukemia and acute lymphoblastic leukemia in vitro and in vivo
    American Society of Hematology ; 2009
    In:  Blood Vol. 113, No. 19 ( 2009-05-07), p. 4656-4666
    Details
    In: Blood, American Society of Hematology, Vol. 113, No. 19 ( 2009-05-07), p. 4656-4666
    Abstract: Therapeutic options for advanced B-cell acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL) are limited. Available treatments can also deplete T lymphocytes, leaving patients at risk of life-threatening infections. In the National Cancer Institute cell line screen, the structurally unique natural product silvestrol produces an unusual pattern of cytotoxicity that suggests activity in leukemia and selectivity for B cells. We investigated silvestrol efficacy using primary human B-leukemia cells, established B-leukemia cell lines, and animal models. In CLL cells, silvestrol LC50 (concentration lethal to 50%) is 6.9 nM at 72 hours. At this concentration, there is no difference in sensitivity of cells from patients with or without the del(17p13.1) abnormality. In isolated cells and whole blood, silvestrol is more cytotoxic toward B cells than T cells. Silvestrol causes early reduction in Mcl-1 expression due to translational inhibition with subsequent mitochondrial damage, as evidenced by reactive oxygen species generation and membrane depolarization. In vivo, silvestrol causes significant B-cell reduction in Eμ-Tcl-1 transgenic mice and significantly extends survival of 697 xenograft severe combined immunodeficient (SCID) mice without discernible toxicity. These data indicate silvestrol has efficacy against B cells in vitro and in vivo and identify translational inhibition as a potential therapeutic target in B-cell leukemias.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2008-09-175430
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
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  • 5
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    Oral Administration of a Small Molecule Targeted to Block proNGF Binding to p75 Promotes Myelin Sparing and Functional Recovery after Spinal Cord Injury
    Society for Neuroscience ; 2013
    In:  The Journal of Neuroscience Vol. 33, No. 2 ( 2013-01-09), p. 397-410
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 33, No. 2 ( 2013-01-09), p. 397-410
    Abstract: The lack of effective therapies for spinal cord injury points to the need for identifying novel targets for therapeutic intervention. Here we report that a small molecule, LM11A-31, developed to block proNGF-p75 interaction and p75-mediated cell death crosses the blood–brain barrier efficiently when delivered orally. Administered starting 4 h postinjury, LM11A-31 promotes functional recovery without causing any toxicity or increased pain in a mouse model of spinal contusion injury. In both weight-bearing open-field tests and nonweight-bearing swim tests, LM11A-31 was effective in improving motor function and coordination. Such functional improvement correlated with a 〉 50% increase in the number of surviving oligodendrocytes and myelinated axons. We also demonstrate that LM11A-31 indeed inhibits proNGF-p75 interaction in vivo , thereby curtailing the JNK3-mediated apoptotic cascade. These results thus highlight p75 as a novel therapeutic target for an orally delivered treatment for spinal cord injury.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.0399-12.2013
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2013
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 6
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    NF-κB p50 (nfkb1) contributes to pathogenesis in the Eμ-TCL1 mouse model of chronic lymphocytic leukemia
    American Society of Hematology ; 2017
    In:  Blood Vol. 130, No. 3 ( 2017-07-20), p. 376-379
    Details
    In: Blood, American Society of Hematology, Vol. 130, No. 3 ( 2017-07-20), p. 376-379
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2017-01-761130
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2017
    detail.hit.zdb_id: 1468538-3
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  • 7
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    A Novel Inhibitor of BET Family Bromodomains Demonstrates In Vivo and I n Vi tro Potency in B-Cell Malignancies
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 318-318
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 318-318
    Abstract: Chronic Lymphocytic Leukemia (CLL) is a B-cell malignancy with aberrant activation of the B-cell receptor (BCR) pathway. Despite durable remissions with targeted therapies (e.g., ibrutinib) in CLL, it remains an incurable disease. Epigenetic modifications, including DNA methylation and dysregulation of chromatin regulators have been shown to contribute to the neoplastic phenotype and the differential biologic behavior of tumor cells, including leukemia. An additional layer of epigenetic complexity in cancer cells is the acquisition of super-enhancer regions enriched at genes with known oncogenic function including MYC and BCL2. Super-enhancers in multiple myeloma cells and other tumors have been found strongly enriched for binding of BRD4, a member of the human bromodomain and extraterminal (BET) domain family of proteins which includes BRD2, BRD3, BRD4, and the testis-specific member BRDT. BRD4 binds to acetylated lysines on histones and regulates the expression of important oncogenes (e.g., MYC and BCL2). We investigated the therapeutic benefit of BET inhibition in cell culture and in vivo disease models of leukemia/lymphoma using PLX51107, a novel BRD4 inhibitor with unique binding mode. Results: We report that BRD4 is significantly overexpressed in CLL patient-derived B-cells compared to B-cells from healthy donors on both transcript and protein level (p 〈 .001). RNA-seq analysis of 55 CLL patients revealed expression of various BRD4 isoforms with marked abundance of BRD4-long and BRD4-short. Next we sought to investigate the anti-tumor activity of PLX51107 in multiple malignant B-cell lines and patient-derived CLL cells. PLX51107 inhibited cell growth in MEC1, OCI-Ly2 and OCI-Ly6 (p 〈 .001) dose-dependently with IC50 of 1.0 ± 0.09, 1.2 ± 0.05, 1.8 ± 0.05 μM, respectively. Notably, PLX51107 antagonized CpG-induced increase in cell proliferation of primary CLL cells (p 〈 .01) which was consistent with the downmodulation of MYC and MCL1 along with the accumulation of the cyclin-dependent kinase inhibitor p21 and IκBα (p 〈 .005). Furthermore, the efficacy of PLX51107 to disrupt survival signaling from the microenvironment was investigated under co-culture conditions with two different bone marrow stroma cell lines, wherein PLX51107 treatment significantly induced cytotoxicity in B-CLL cells (p 〈 .01) without affecting stromal cell viability. By employing microarray analysis we identified possible novel targets of BRD4 in CLL. Validation of those targets is currently ongoing. Particularly, Bruton's tyrosine kinase (BTK) and phospholipase C gamma 2 (PLCG2) were markedly decreased with PLX51107 treatment (p 〈 .005), thereby signifying potential therapeutic effect(s) for dual targeting of BRD4 and BCR-associated kinases to achieve deeper and durable responses in relapsed/refractory B-cell malignancies. Lastly, anti-tumor effects of BRD4 inhibition were evaluated in vivo using Eμ-TCL1 and cMYC/TCL1 adoptive transfer models of leukemia and lymphoma, respectively. In the Eμ-TCL1 engraftment model of aggressive CLL, PLX51107 treatment resulted in prolonged survival (p 〈 .001) accompanied with decreased disease burden, lymphocyte infiltration and proliferation when compared to vehicle-treated mice. Next, the cMYC/TCL1 adoptive transfer mouse model was used to evaluate BRD4 inhibition in a highly penetrant, malignant leukemia/lymphoma phenotype analogous to high grade lymphoma wherein PLX51107 prolonged survival (p 〈 .0001), decreased peripheral lymphocyte counts and neoplastic cell infiltration and proliferation in both spleen and lymph nodes. Conclusion: Collectively our findings reveal BRD4 as a valid and novel target for epigenetic therapy directed against core transcriptional programs in malignant/proliferating B-cells and provide support for use of PLX51107 as an effective treatment in clinical trials for relapsed/refractory CLL patients and related aggressive forms of B-cell malignancies, with the ultimate goal of improving the outcome of these patients. Disclosures Byrd: Acerta Pharma BV: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.318.318
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
    detail.hit.zdb_id: 1468538-3
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  • 8
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    The BTK Inhibitor ARQ 531 Targets Ibrutinib-Resistant CLL and Richter Transformation
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Discovery Vol. 8, No. 10 ( 2018-10-01), p. 1300-1315
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 8, No. 10 ( 2018-10-01), p. 1300-1315
    Abstract: Targeted inhibition of Bruton tyrosine kinase (BTK) with the irreversible inhibitor ibrutinib has improved outcomes for patients with hematologic malignancies, including chronic lymphocytic leukemia (CLL). Here, we describe preclinical investigations of ARQ 531, a potent, reversible inhibitor of BTK with additional activity against Src family kinases and kinases related to ERK signaling. We hypothesized that targeting additional kinases would improve global inhibition of signaling pathways, producing more robust responses. In vitro treatment of patient CLL cells with ARQ 531 decreases BTK-mediated functions including B-cell receptor (BCR) signaling, viability, migration, CD40 and CD86 expression, and NF-κB gene transcription. In vivo, ARQ 531 was found to increase survival over ibrutinib in a murine Eμ-TCL1 engraftment model of CLL and a murine Eμ-MYC/TCL1 engraftment model resembling Richter transformation. Additionally, ARQ 531 inhibits CLL cell survival and suppresses BCR-mediated activation of C481S BTK and PLCγ2 mutants, which facilitate clinical resistance to ibrutinib. Significance: This study characterizes a rationally designed kinase inhibitor with efficacy in models recapitulating the most common mechanisms of acquired resistance to ibrutinib. Reversible BTK inhibition is a promising strategy to combat progressive CLL, and multikinase inhibition demonstrates superior efficacy to targeted ibrutinib therapy in the setting of Richter transformation. Cancer Discov; 8(10); 1300–15. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1195
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-17-1409
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2607892-2
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  • 9
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    BRD4 Profiling Identifies Critical Chronic Lymphocytic Leukemia Oncogenic Circuits and Reveals Sensitivity to PLX51107, a Novel Structurally Distinct BET Inhibitor
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Discovery Vol. 8, No. 4 ( 2018-04-01), p. 458-477
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 8, No. 4 ( 2018-04-01), p. 458-477
    Abstract: Bromodomain and extra-terminal (BET) family proteins are key regulators of gene expression in cancer. Herein, we utilize BRD4 profiling to identify critical pathways involved in pathogenesis of chronic lymphocytic leukemia (CLL). BRD4 is overexpressed in CLL and is enriched proximal to genes upregulated or de novo expressed in CLL with known functions in disease pathogenesis and progression. These genes, including key members of the B-cell receptor (BCR) signaling pathway, provide a rationale for this therapeutic approach to identify new targets in alternative types of cancer. Additionally, we describe PLX51107, a structurally distinct BET inhibitor with novel in vitro and in vivo pharmacologic properties that emulates or exceeds the efficacy of BCR signaling agents in preclinical models of CLL. Herein, the discovery of the involvement of BRD4 in the core CLL transcriptional program provides a compelling rationale for clinical investigation of PLX51107 as epigenetic therapy in CLL and application of BRD4 profiling in other cancers. Significance: To date, functional studies of BRD4 in CLL are lacking. Through integrated genomic, functional, and pharmacologic analyses, we uncover the existence of BRD4-regulated core CLL transcriptional programs and present preclinical proof-of-concept studies validating BET inhibition as an epigenetic approach to target BCR signaling in CLL. Cancer Discov; 8(4); 458–77. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 371
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-17-0902
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2607892-2
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  • 10
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    Errata
    Wiley ; 1986
    In:  Muscle & Nerve Vol. 9, No. 7 ( 1986-09), p. 648-649
    Details
    In: Muscle & Nerve, Wiley, Vol. 9, No. 7 ( 1986-09), p. 648-649
    Type of Medium: Online Resource
    ISSN: 0148-639X , 1097-4598
    URL: Issue
    URL: Journal
    URL: Article
    DOI: 10.1002/mus.v9:7
    DOI: 10.1002/(ISSN)1097-4598
    DOI: 10.1002/mus.880090712
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 1986
    detail.hit.zdb_id: 1476641-3
    SSG: 12
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