BET bromodomain inhibition rescues erythropoietin differentiation of human erythroleukemia cell line UT7

Goupille, Olivier; Penglong, Tipparat; Lefevre, Carine; Granger, Marine; Kadri, Zahra; Fucharoen, Suthat; Maouche‐Chrétien, Leïla; Leboulch, Philippe; Chrétien, Stany

doi:10.1016/j.bbrc.2012.10.112

Cited by 15 publications

(7 citation statements)

References 19 publications

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“…In vitro experiments with BRD inhibitors, such as JQ1, have demonstrated these agents to carry anti-leukemic activity (63). Consistent with this, JQ1 treatment of UT7, a human erythroleukemia cell line, was able to rescue erythropoietin differentiation within a matter of two days (64). This also highlights the importance of a cellular erythroid cycle break mediated by c-MYC inhibition before initiation of the erythropoiesis program.…”

Section: Pathophysiologysupporting

confidence: 60%

Erythroleukemia-historical perspectives and recent advances in diagnosis and management

et al. 2018

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Acute erythroleukemia is a rare form of acute myeloid leukemia recognized by its distinct phenotypic attribute of erythroblastic proliferation. After a century of its descriptive history, many diagnostic, prognostic, and therapeutic implications relating to this unique leukemia subset remain uncertain. The rarity of the disease and the simultaneous involvement of its associated myeloid compartment have complicated in vitro studies of human erythroleukemia cell lines. Although murine and cell line erythroleukemia models have provided valuable insights into pathophysiology, translation of these concepts into treatment are not forthcoming. Integration of knowledge gained through a careful study of these models with more recent data emerging from molecular characterization will help elucidate key mechanistic pathways and provide a much needed framework that accounts for erythroid lineage-specific attributes. In this article, we discuss the evolving diagnostic concept of erythroleukemia, translational aspects of its pathophysiology, and promising therapeutic targets through an appraisal of the current literature.

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Section: Pathophysiologysupporting

confidence: 60%

Erythroleukemia-historical perspectives and recent advances in diagnosis and management

et al. 2018

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“…Their deregulation may result in various cancers, inflammatory diseases, metabolic diseases and tissue degeneration, involving the abnormal stimulation of transcriptional elongation of certain target genes including MYC and BCL2 oncogenes. 36 Further studies with ( þ )-JQ1 validated BET bromodomain targeting as a promising therapeutic strategy in BL, 27 glioblastoma, 37 erythroleukemia, 38 high-risk acute lymphoblastic leukemia 39 and in aggressive B-cell lymphoma. 40 CPI203 is a BET inhibitor that has shown superior bioavailability with oral or intraperitoneal administration.…”

Section: Discussionmentioning

confidence: 99%

Synergistic antitumor activity of lenalidomide with the BET bromodomain inhibitor CPI203 in bortezomib-resistant mantle cell lymphoma

et al. 2014

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Bortezomib therapy has shown promising clinical activity in mantle cell lymphoma (MCL), but the development of resistance to proteasome inhibition may limit its efficacy. To unravel the factors involved in the acquisition of bortezomib resistance in vivo, immunodeficient mice were engrafted with a set of MCL cell lines with different levels of sensitivity to the drug, followed by gene expression profiling of the tumors and functional validation of the identified gene signatures. We observed an increased tumorigenicity of bortezomib-resistant MCL cells in vivo, which was associated with plasmacytic differentiation features, like interferon regulatory factor 4 (IRF4) and Blimp-1 upregulation. Lenalidomide was particularly active in this subgroup of tumors, targeting IRF4 expression and plasmacytic differentiation program, thus overcoming bortezomib resistance. Moreover, repression of the IRF4 target gene MYC in bortezomib-resistant cells by gene knockdown or treatment with CPI203, a BET (bromodomain and extra terminal) bromodomain inhibitor, synergistically induced cell death when combined with lenalidomide. In mice, addition of CPI203 to lenalidomide therapy further decreased tumor burden, involving simultaneous MYC and IRF4 downregulation and apoptosis induction. Together, these results suggest that exacerbated IRF4/MYC signaling is associated to bortezomib resistance in MCL in vivo and warrant clinical evaluation of lenalidomide plus BET inhibitor combination in MCL cases refractory to proteasome inhibition.

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“…We showed that BET proteins in primary ASM cells are important in controlling ASM cell proliferation both in healthy and asthmatic cells. Previous studies have mainly focused on cancerous cell lines, where JQ1/SGCBD01 inhibited cellular proliferation of NUT midline carcinoma ( 35 ), lung cancer cells ( 36 ), acute myeloid leukemia cells ( 37 ), and a human leukemic cell line (UT7) ( 38 ). This mechanism is documented to occur via a decrease in either c-Myc expression or c-Myc association with a number of proliferative gene promoters.…”

Section: Discussionmentioning

confidence: 99%

BET Bromodomains Regulate Transforming Growth Factor-β-induced Proliferation and Cytokine Release in Asthmatic Airway Smooth Muscle

Perry

Durham

Austin

et al. 2015

Journal of Biological Chemistry

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Background: Airway smooth muscle (ASM) from asthmatics is in a hyperproliferative state and releases more cytokines than healthy individuals.Results: Inhibition of BET bromodomains reduces ASM proliferation and cytokine release by reducing Brd4 binding to the promoter regions of IL-6 and CXCL8.Conclusion: BET bromodomain mimics inhibit aberrant ASM proliferation and inflammation in asthmatic patients.Significance: These compounds may reduce airway remodeling in asthma.

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BET bromodomain inhibition rescues erythropoietin differentiation of human erythroleukemia cell line UT7

Cited by 15 publications

References 19 publications

Erythroleukemia-historical perspectives and recent advances in diagnosis and management

Erythroleukemia-historical perspectives and recent advances in diagnosis and management

Synergistic antitumor activity of lenalidomide with the BET bromodomain inhibitor CPI203 in bortezomib-resistant mantle cell lymphoma

BET Bromodomains Regulate Transforming Growth Factor-β-induced Proliferation and Cytokine Release in Asthmatic Airway Smooth Muscle

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