The Expanding Role of the BCL6 Oncoprotein as a Cancer Therapeutic Target

Cárdenas, Mariano; Oswald, Erin; Yu, Wenbo; Xue, Fengtian; MacKerell, Alexander D.; Melnick, Ari

doi:10.1158/1078-0432.ccr-16-2071

Cited by 149 publications

(186 citation statements)

References 63 publications

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“…B-Cell Lymphoma 6 (BCL-6) is a master transcriptional repressor and an oncoprotein which, directly or indirectly inhibits the expression of more than 1000 genes. It is a key regulator gene in multiple myeloma [41,42]. BCL-6 has also been reported to be an antiviral resistance repressor in follicular T helper cells [43].…”

Section: Discussionmentioning

confidence: 99%

Expression of the miR-302/367 microRNA cluster is regulated by a conserved long non-coding host gene

Rahimi

Füchtbauer

Fathi

et al. 2018

Preprint

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MicroRNAs (miRNAs) are important regulators of cellular functions. MiR-302/367 is a polycistronic miRNA cluster including miR-302b/c/a/d (collectively termed miR-302s) and miR-367. The cluster is located in the intron of a non-coding host gene. MiR-302s have been shown to repress mRNAs required for differentiation and to induce pluripotency in somatic cells. The stem cell specific transcription factors OCT4, SOX2 and Nanog drive miR-302s expression, however, the reported expression in human and mice indicates a more complex transcriptional regulation. Here we investigate the transcriptional control and the processing of the miR-302 host gene. The murine miR-302 host gene is alternatively spliced, polyadenylated and exported from the nucleus. The regulatory sequences extend at least 2 kb upstream of the transcription start side and contain several conserved binding sites for both transcriptional activators and repressors. Reporter constructs with different upstream regions revealed a significant influence of the more distant regulatory sequences in pluripotent stem cells. The gene structure and regulatory elements like binding sites for activating and repressing transcriptional regulators, splice, and polyadenylation signals are highly conserved between mouse and human. So far, no miR-302 independent function has been annotated for the miR-302 host gene and we hypothesize that the complex and differential regulation of the miRNA transcription and processing might the reason for its conservation. Thus, regulation or micro-RNA expression might be a so far less recognized function of non-coding RNA genes. Author SummaryNon-coding RNAs constitute a large part of the mammalian genome. Interestingly, some long non-coding RNAs (lncRNA) are transcribed and processed in the same way as mRNAs but lack an open reading frame. Here we give evidence that a so far less recognized function of such lncRNAs could be to supply microRNAs with the complex transcriptional control and processing required for their intricate expression. As an example, we analyzed the regulatory sequences of the miR-302/367 host gene. MiR-302/367 is a microRNA cluster involved in the regulation of stem cells and cellular differentiation. We show here that the regulatory region is much more complex than anticipated, a complexity that can not be conferred alone by any of the stem cell specific transcription factors which were so far associated with the expression of miR-302/367.

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Section: Discussionmentioning

confidence: 99%

Expression of the miR-302/367 microRNA cluster is regulated by a conserved long non-coding host gene

Rahimi

Füchtbauer

Fathi

et al. 2018

Preprint

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“…The MAPK8 gene is a member of the MAP kinase and JNK family, and involved in various cellular processes including cell proliferation, differentiation, and apoptosis [25,26]. The BCOR gene encodes a co-repressor of BCL6, a transcriptional repressor that is required for formation of germinal centres [27,28] and silences various genes involved in the cell cycle and apoptosis [29]. The target genes of miR-486 included PIK3R1 , one of the oncogenes that promotes cell proliferation and tumour cell invasion [30].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of miRNA and protein profiles within exosomes derived from canine lymphoid tumour cell lines

Asada

Tomiyasu

Uchikai³

et al. 2018

Preprint

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17Exosomes are small extracellular vesicles released from almost all cell types, 18 which play roles in cell-cell communication. Recent studies have suggested that 19 microenvironmental crosstalk mediated by exosomes is an important factor in the 20 escape of tumour cells from the anti-tumour immune system in human haematopoietic 21 malignancies. Here, we conducted comprehensive analysis of the miRNA and protein 22 profiles within the exosomes released from four canine lymphoid tumour cell lines as a 23 model of human lymphoid tumours. The results showed that the miRNAs and proteins 24 abundantly contained in exosomes were similar among the four cell lines. However, the 25 profiles of miRNA within exosomes differed among the cell lines and reflected the 26 expression pattern of miRNAs of the parent cells. In the comparison of the amounts of 27 miRNAs and proteins among the cell lines, those of three miRNAs (miR-151, 28 miR-8908a-3p, and miR-486) and CD82 protein differed between exosomes derived 29 from vincristine-sensitive and resistant cell lines. Further investigations are needed to 30 elucidate the biological functions of the exosomal contents in the microenvironmental 31 crosstalk of lymphoid tumours.32 3 33 Introduction 34 Exosomes are small extracellular vesicles released from almost all cell types, 35 including immune cells and tumour cells [1], as the intracellular endosome component. 36 Although exosomes were initially considered cellular waste, they have been shown to 37 contain various molecules from the original cells, including proteins, functional mRNAs 38 and miRNAs, and deliver these biological messages into the recipient cells [1,2]. To 39 date, it has also been reported that tumour cells release a number of exosomes and they 40 stimulate tumour cell growth and modify the immune cell response to promote tumour 41 progression and metastasis in several human tumors, including colorectal cancer [3], 42 breast cancer [4], melanoma [5], and pancreatic cancer [6]. Thus, the interaction 43 between tumour cell-derived exosomes and recipient cells in the microenvironment of 44 solid tumours is considered an important factor in tumour progression, metastasis, cell 45 survival, and escape from the anti-tumour immune system. 46 Exosomes have also been suggested to play important roles in the 47 microenvironmental crosstalk of human haematopoietic tumours, including leukaemia 48 and lymphoma [7,8]. It has been reported that exosomes derived from acute/chronic 49 myeloid leukaemia and lymphoma cells inactivate natural killer cells and suppress the 50 anti-tumour immune response [7-9]. In addition, exosomes have been reported to be 4 51 associated with drug resistance in these tumours [7]. For instance, it was reported that 52 exosomes derived from imatinib-resistant chronic leukaemia cells could confer 53 imatinib-resistance traits into sensitive cells by delivering miR-365 [10]. It was also 54 reported that exosomes derived from bone marrow stromal cells decreased the 55 sensitivity of acute lymphoblasti...

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“…Fortunately, a higher permeability CP series was identified from fragment screening followed by structure Additionally, combination treatment with a BCL6 inhibitor or degrader may be what is required to elicit a marked phenotypic response in the disease setting, as combinations with inhibitors of EZH2, BCL2 or other oncogenic factors have been previously suggested. 7,40 In summary, BCL6 inhibitors were developed with high activity, good cellular potency, proven in-cell target engagement, excellent selectivity, and significant exposure in the nuclear subcellular fractions, yet did not induce significant antiproliferative activity in a DLBCL cell line panel. A BCL6 PROTAC was designed with similar attributes and shown to effectively degrade BCL6 in all subcellular fractions with the exception of a residual BCL6 population but also failed to induce significant phenotypic response.…”

Section: Caco2mentioning

confidence: 99%

Development of a Novel B-Cell Lymphoma 6 (BCL6) PROTAC To Provide Insight into Small Molecule Targeting of BCL6

et al. 2018

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B-cell lymphoma 6 (BCL6) inhibition is a promising mechanism for treating hematological cancers but high quality chemical probes are necessary to evaluate its therapeutic potential. Here we report potent BCL6 inhibitors that demonstrate cellular target engagement and exhibit exquisite selectivity for BCL6 based on mass spectrometry analyses following chemical proteomic pulldown. Importantly, a proteolysis-targeting chimera (PROTAC) was also developed and shown to significantly degrade BCL6 in a number of The structures of BCL6 BTB domain bound to compounds 1, 2 and 9 have been deposited in the Protein Data Bank with PDB accession codes 6ew6, 6ew7 and 6ew8, respectively. AUTHOR INFORMATIONCorresponding Author

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The Expanding Role of the BCL6 Oncoprotein as a Cancer Therapeutic Target

Cited by 149 publications

References 63 publications

Expression of the miR-302/367 microRNA cluster is regulated by a conserved long non-coding host gene

Expression of the miR-302/367 microRNA cluster is regulated by a conserved long non-coding host gene

Comprehensive analysis of miRNA and protein profiles within exosomes derived from canine lymphoid tumour cell lines

Development of a Novel B-Cell Lymphoma 6 (BCL6) PROTAC To Provide Insight into Small Molecule Targeting of BCL6

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