Dual Targeting of Oncogenic Activation and Inflammatory Signaling Increases Therapeutic Efficacy in Myeloproliferative Neoplasms

Kleppe, Maria; Koche, Richard P.; Zou, Lihua; Galen, Peter van; Hill, Corinne E.; Dong, Lauren; Groote, Sofie De; Papalexi, Efthymia; Somasundara, Amritha Varshini Hanasoge; Cordner, Keith B.; Keller, Matthew C.; Farnoud, Noushin; Medina, Juan C.; McGovern, Erin; Reyes, Jaime M.; Roberts, Justin; Witkin, Matthew D.; Rapaport, Franck; Teruya-Feldstein, Julie; Qi, Jun; Rampal, Raajit K.; Bernstein, B; Bradner, James E.; Levine, Ross L.

doi:10.1016/j.ccell.2018.03.024

Cited by 107 publications

(106 citation statements)

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“…In plasmacytomas arising from Gp130 activation alone, activating genetic alterations in the c-MYC locus were recovered in three of ten independently arising tumors (33). Combining JAK and BET inhibitors is a potentially promising strategy for other hematologic malignancies, including JAK2V617-dependent myeloproliferative neoplasms and acute lymphocytic leukemia (ALL) characterized by IL7R activation (35)(36)(37)(38). In the ALL models, JQ-1 suppressed STAT5dependent signaling and improved survival; significantly at relapse, these tumors showed reactivation of STAT5 signaling indicating a feedback upregulation of JAK-STAT signaling.…”

Section: Discussionmentioning

confidence: 99%

The Novel Bromodomain and Extraterminal Domain Inhibitor INCB054329 Induces Vulnerabilities in Myeloma Cells That Inform Rational Combination Strategies

Stubbs

Burn

Sparks

et al. 2019

Clinical Cancer Research

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Bromodomain and extraterminal domain (BET) proteins regulate the expression of many cancer-associated genes and pathways; BET inhibitors have demonstrated activity in diverse models of hematologic and solid tumors. We report the preclinical characterization of INCB054329, a structurally distinct BET inhibitor that has been investigated in phase I clinical trials. We used multiple myeloma models to investigate vulnerabilities created by INCB054329 treatment that could inform rational combinations. In addition to c-MYC, INCB054329 decreased expression of oncogenes and, which are deregulated in t(4;14)-rearranged cell lines. The profound suppression of sensitized the t(4;14)-positive cell line OPM-2 to combined treatment with a fibroblast growth factor receptor inhibitor In addition, we show that BET inhibition across multiple myeloma cell lines resulted in suppressed interleukin (IL)-6 Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling. INCB054329 displaced binding of BRD4 to the promoter of IL6 receptor (IL6R) leading to reduced levels of IL6R and diminished signaling through STAT3. Combination with JAK inhibitors (ruxolitinib or itacitinib) further reduced JAK-STAT signaling and synergized to inhibit myeloma cell growth and This combination potentiated tumor growth inhibition , even in the MM1.S model of myeloma that is not intrinsically sensitive to JAK inhibition alone. Preclinical data reveal insights into vulnerabilities created in myeloma cells by BET protein inhibition and potential strategies that can be leveraged in clinical studies to enhance the activity of INCB054329.

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Section: Discussionmentioning

confidence: 99%

The Novel Bromodomain and Extraterminal Domain Inhibitor INCB054329 Induces Vulnerabilities in Myeloma Cells That Inform Rational Combination Strategies

Stubbs

Burn

Sparks

et al. 2019

Clinical Cancer Research

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“…In a mouse MPN model combining the BET inhibitor JQ1 with ruxolitinib showed improved efficacy relative to monotherapy with either agent. 186 In patients with MPN, mutations of JAK2 and the metabolic enzyme isocitrate dehydrogenase (IDH) have a poor outcome, and combined inhibition of JAK2 and IDH has utility in a murine model. 187 Such combinations might also be useful to induce remission in severe autoimmune disease.…”

Section: What's Aheadmentioning

confidence: 99%

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

Gadina

Johnson

Schwartz

et al. 2018

Journal of Leukocyte Biology

123

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In this era, it is axiomatic that cytokines have critical roles in cellular development and differentiation, immune homeostasis, and host defense. Equally, dysregulation of cytokines is known to contribute to diverse inflammatory and immune-mediated disorders. In fact, the past 20 years have witnessed the rapid translation of basic discoveries in cytokine biology to multiple successful biological agents (mAbs and recombinant fusion proteins) that target cytokines. These targeted therapies have not only fundamentally changed the face of multiple immune-mediated diseases but have also unequivocally established the role of specific cytokines in human disease; cytokine biologists have many times over provided remarkable basic advances with direct clinical benefit. Numerous cytokines rely on the JAK-STAT pathway for signaling, and new, safe, and effective small molecule inhibitors have been developed for a range of disorders. In this review, we will briefly summarize basic discoveries in cytokine signaling and briefly comment on some major unresolved issues. We will review clinical data pertaining to the first generation of JAK inhibitors and their clinical indications, discuss additional opportunities for targeting this pathway, and lay out some of the challenges that lie ahead.

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“…The JAK/STAT signaling pathway plays an important role in regulating cellular processes, such as apoptosis, differentiation, proliferation and migration [36]. The abnormal activation of JAK/STAT led to the occurrence and development of various types of cancers, including hematological malignancies and solid tumors [[37], [38], [39]].…”

Section: Discussionmentioning

confidence: 99%

The Long Noncoding RNA MEG3 and its Target miR-147 Regulate JAK/STAT Pathway in Advanced Chronic Myeloid Leukemia

Yang

Liu

et al. 2018

EBioMedicine

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BackgroundLong non-coding (lnc) RNAs plays an important role in chronic myeloid leukemia (CML). In this study, we aimed to uncover the mechanism of the lncRNA maternally expressed 3 (MEG3) and its target microRNA-147 (miR-147) in CML.MethodsSixty CML patients and 10 healthy donors were included in the study. The methylation of MEG3 and miR-147 promoter was determined by methylation-specific PCR. The relationship of MEG3 and miR-147 was explored by luciferase assay. The interactions of proteins were studied by RNA pull-down assay, RNA immunoprecipitation and co-immunoprecipitation.FindingsPatients in accelerated phase CML (CML-AP) and blast phase CML (CML-BP) showed lower expressions of MEG3 and miR-147 and higher expressions of DNMT1, DNMT3B, MBD2, MECP2 and HDAC1 compared to the controls. These patients also showed a higher degree of methylation of MEG3 and miR-147 while there was a reduction after chidamide treatment. Furthermore, the overexpression of MEG3 and miR-147 inhibited cell proliferation both in vivo and in vitro, promoted apoptosis and decreased the expressions of DNMT1, DNMT3A, DNMT3B, MBD2, HDAC1 and MECP2. We also found MEG3 interacted with DNMT1, JAK2, STAT3, HDAC1, and TYK2, and JAK2 was bound to STAT3, STAT5 and MYC. More interestingly, JAK2 was bound to TYK2 by the bridge of MEG3.InterpretationLncRNA MEG3 and its target miR-147 may serve as a novel therapeutic target for CML blast crisis, and chidamide might have a potential clinical application in treating CML blast crisis.

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Dual Targeting of Oncogenic Activation and Inflammatory Signaling Increases Therapeutic Efficacy in Myeloproliferative Neoplasms

Cited by 107 publications

References 0 publications

The Novel Bromodomain and Extraterminal Domain Inhibitor INCB054329 Induces Vulnerabilities in Myeloma Cells That Inform Rational Combination Strategies

The Novel Bromodomain and Extraterminal Domain Inhibitor INCB054329 Induces Vulnerabilities in Myeloma Cells That Inform Rational Combination Strategies

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

The Long Noncoding RNA MEG3 and its Target miR-147 Regulate JAK/STAT Pathway in Advanced Chronic Myeloid Leukemia

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