Molecular targeting of the PKC‐<i>β</i> inhibitor enzastaurin (LY317615) in multiple myeloma involves a coordinated downregulation of MYC and IRF4 expression

Verdelli, Donata; Nobili, Lucia; Todoerti, Katia; Intini, Daniela; Cosenza, Maria; Civallero, Monica; Bertacchini, Jessika; Deliliers, Giorgio Lambertenghi; Sacchi, Stefano; Lombardi, Luigia; Neri, Antonino

doi:10.1002/hon.875

Cited by 19 publications

(9 citation statements)

References 18 publications

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“…In addition, MYC and IRF4 form a positive autoregulatory loop (Figures 1 & 2), implying that any therapy targeting IRF4 transcription would have the added benefit of decreasing MYC transcription. Of interest in this regard is a recent study showing that the protein kinase Cβ inhibitor, enzastaurin, has anti-proliferative and pro-apoptotic activity in MM and coordinately downregulates expression of both IRF4 and MYC (85). …”

Section: Clinical-translational Advancesmentioning

confidence: 99%

IRF4: Immunity. Malignancy! Therapy?

Shaffer

Emre

Romesser

et al. 2009

Clinical Cancer Research

169

147

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IRF4, a member of the Interferon Regulatory Factor (IRF) family of transcription factors, is expressed in cells of the immune system, where it transduces signals from various receptors to activate or repress gene expression. IRF4 expression is a key regulator of several steps in lymphoid-, myeloid-, and dendritic-cell differentiation, including the differentiation of mature B cells into antibody-secreting plasma cells. IRF4 expression is also associated with many lymphoid malignancies, with recent evidence pointing to an essential role in multiple myeloma, a malignancy of plasma cells. Interference with IRF4 expression is lethal to multiple myeloma cells, irrespective of their genetic etiology, making IRF4 an '' Achilles' heel'' that may be exploited therapeutically.

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Section: Clinical-translational Advancesmentioning

confidence: 99%

IRF4: Immunity. Malignancy! Therapy?

Shaffer

Emre

Romesser

et al. 2009

Clinical Cancer Research

169

147

View full text Add to dashboard Cite

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Section: Irf4 Is Constitutively Expressed In Ptcl and Drives Prolifermentioning

confidence: 99%

“…Enzastaurin also has been reported to downregulate IRF4 expression in multiple myeloma cells. 22 Unlike both normal T cells and myeloma cells, however, PTCL cells were resistant to the effects of enzastaurin in inhibiting IRF4 expression.In multiple myeloma cells, IRF4 and Myc regulate each other's expression to drive tumor cell proliferation. 10 We therefore examined whether this autoregulatory circuit was present in PTCL cells.…”

mentioning

confidence: 99%

The oncogenic transcription factor IRF4 is regulated by a novel CD30/NF-κB positive feedback loop in peripheral T-cell lymphoma

Boddicker

Kip

Xing

et al. 2015

Blood

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• The NF-kB subunits p52 and RelB increase IRF4 promoter activity and expression in PTCL cells.• A positive feedback loop involving CD30, NF-kB, and IRF4 drives PTCL cell proliferation and can be blocked by NF-kB inhibitors.Peripheral T-cell lymphomas (PTCLs) are generally aggressive non-Hodgkin lymphomas with poor overall survival rates following standard therapy. One-third of PTCLs express interferon regulatory factor-4 (IRF4), a tightly regulated transcription factor involved in lymphocyte growth and differentiation. IRF4 drives tumor growth in several lymphoid malignancies and has been proposed as a candidate therapeutic target. Because direct IRF4 inhibitors are not clinically available, we sought to characterize the mechanism by which IRF4 expression is regulated in PTCLs. We demonstrated that IRF4 is constitutively expressed in PTCL cells and drives Myc expression and proliferation. Using an inhibitor screen, we identified nuclear factor kB (NF-kB) as a candidate regulator of IRF4 expression and cell proliferation. We then demonstrated that the NF-kB subunits p52 and RelB were transcriptional activators of IRF4. Further analysis showed that activation of CD30 promotes p52 and RelB activity and subsequent IRF4 expression. Finally, we showed that IRF4 transcriptionally regulates CD30 expression. Taken together, these data demonstrate a novel positive feedback loop involving CD30, NF-kB, and IRF4; further evidence for this mechanism was demonstrated in human PTCL tissue samples. Accordingly, NF-kB inhibitors may represent a clinical means to disrupt this feedback loop in IRF4-positive PTCLs. (Blood. 2015; 125(20):3118-3127) Introduction Peripheral T-cell lymphomas (PTCLs) are aggressive non-Hodgkin lymphomas (NHLs) characterized by poor overall survival rates. [1][2][3] Most patients are treated with anthracycline-based chemotherapy regimens originally designed for B-cell lymphomas. Five-year overall survival rates vary somewhat by subtype but average ;35%. The possibility of individualized targeted therapy holds promise, but advances have been hindered by the fact that few therapeutic targets have been identified and validated in PTCLs. Our group's approach to this challenge has been to characterize the genetics of PTCLs to identify novel biomarkers and therapeutic targets. We have focused particularly on chromosomal translocations, which have played a major role in identifying diagnostic, prognostic, and theranostic biomarkers in hematologic neoplasms in general (eg, BCR-ABL) and PTCLs specifically (ALK rearrangements). 4,5 We previously discovered a recurrent translocation in PTCL, t(6;14)(p25.3;q11.2), that juxtaposes the interferon regulatory factor-4 (IRF4) and T-cell receptor-a (TRA) genes and is associated with increased IRF4 expression. 6 Because TRA translocation partners typically function as oncogenes in T-cell malignancies, we postulated that IRF4 plays an oncogenic role in PTCLs.7 IRF4 is a tightly regulated transcription factor involved in growth and differentiation of normal T and B lymp...

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“…The role of PKC in the regulation of immune responses is crucial and many of the PKCi previously or currently trialed in solid cancers have been tested for their effect on hematological diseases and immune cells [205,206]. Farren et al demonstrated that the induction of MDSC in vitro is regulated by the downregulation of PKCbII and hyperactivation of Stat3 [207].…”

Section: Other Inhibitors That Have Targets Outside the Mapk Or Pi3k mentioning

confidence: 98%

Immune consequences of kinase inhibitors in development, undergoing clinical trials and in current use in melanoma treatment

Vella

Andrews

Behren

et al. 2014

Expert Review of Clinical Immunology

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Metastatic malignant melanoma is a frequently fatal cancer. In recent years substantial therapeutic progress has occurred with the development of targeted kinase inhibitors and immunotherapeutics. Targeted therapies often result in rapid clinical benefit however responses are seldom durable. Immune therapies can result in durable disease control but responses may not be immediate. Optimal cancer therapy requires both rapid and durable cancer control and this can likely best be achieved by combining targeted therapies with immunotherapeutics. To achieve this, a detailed understanding of the immune consequences of the various kinase inhibitors, in development, clinical trial and currently used to treat melanoma is required.

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Molecular targeting of the PKC‐β inhibitor enzastaurin (LY317615) in multiple myeloma involves a coordinated downregulation of MYC and IRF4 expression

Cited by 19 publications

References 18 publications

IRF4: Immunity. Malignancy! Therapy?

IRF4: Immunity. Malignancy! Therapy?

The oncogenic transcription factor IRF4 is regulated by a novel CD30/NF-κB positive feedback loop in peripheral T-cell lymphoma

Immune consequences of kinase inhibitors in development, undergoing clinical trials and in current use in melanoma treatment

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