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Fusion transcripts: Unexploited vulnerabilities in cancer?

Opinion

Natasha J. Caplen, Soumya Sundara Rajan, Carla Neckles

Published Online: Aug 13 2019

DOI: 10.1002/wrna.1562

Full article on Wiley Online Library: HTML PDF

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Abstract Gene fusions are an important class of mutations in several cancer types and include genomic rearrangements that fuse regulatory or coding elements from two different genes. Analysis of the genetics of cancers harboring fusion oncogenes and the proteins they encode have enhanced cancer diagnosis and in some cases patient treatment. However, the effect of the complex structure of fusion genes on the biogenesis of the resulting chimeric transcripts they express is not well studied. There are two potential RNA‐related vulnerabilities inherent to fusion‐driven cancers: (a) the processing of the fusion precursor messenger RNA (pre‐mRNA) to the mature mRNA and (b) the mature mRNA. In this study, we discuss the effects that the genetic organization of fusion oncogenes has on the generation of translatable mature RNAs and the diversity of fusion transcripts expressed in different cancer subtypes, which can fundamentally influence both tumorigenesis and treatment. We also discuss functional genomic approaches that can be utilized to identify proteins that mediate the processing of fusion pre‐mRNAs. Furthermore, we assert that an enhanced understanding of fusion transcript biogenesis and the diversity of the chimeric RNAs present in fusion‐driven cancers will increase the likelihood of successful application of RNA‐based therapies in this class of tumors. This article is categorized under: RNA Processing > RNA Editing and Modification RNA Processing > Splicing Regulation/Alternative Splicing RNA in Disease and Development > RNA in Disease

Canonical and alternative splicing events for a representative fusion transcript. Boxes and solid lines indicate exons and introns, respectively. The dashed lines indicate possible splicing events in the context of exons adjacent to a fusion breakpoint

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Potential therapeutic approaches to target EWS‐FLI1 transcripts using nucleic acid analogues or small molecules. The representations of the mechanism of action of nucleic acid analogues are adapted with permission from Lieberman (). Copyright 2018 Springer Nature and encompass some of the major classes of RNA‐based drugs. (a) Antisense oligonucleotides that are typically single‐stranded with a central DNA gapmer region; (b) double‐stranded siRNAs; (c) miRNA mimics; and (d) aptamer‐based analogues such as aptamer‐siRNA conjugates. Representations of the mechanism of actions for (e) RNA‐binding small molecules that modulate the binding of an RNA binding protein (RBP) and (f) bifunctional small molecules that recruit a ribonuclease (RNase)

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(a) Schematic depictions of the EWSR1, FLI1, and EWS‐FLI1 genes. Indicated are the relative size of each exon (upper) and each intron (lower part of each panel). Genes and transcripts (not to scale) are shown 5 to 3′. (b) Schematic depiction of the putative splicing motifs in regions including and adjacent to EWSR1 exons 7 and 8 and FLI1 exon 6 that are involved in EWS‐FLI1 type 1 fusions. Representations are provided by Human Splicing Finder 3.1 (Desmet et al., ) for indicated regions within ENST00000406548 (EWSR1) or ENST00000527786 (FLI1)

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(a) Schematic depictions of representative transcripts expressed from fusion genes generated by chromosomal rearrangements (t11;22)(q24;q12) and t(21;22)(q21;q12) that disrupt the EWSR1 and FLI1 or ERG genes. (Adapted with permission from Sankar and Lessnick (). Copyright 2011 Elsevier) and COSMIC resources (COSMIC). (b) Candidate genes associated with canonical or alternative splicing identified by a RNAi screen of EWS‐FLI1 activity. The median seed corrected Z‐score obtained by the difference between Z_NROB1 and Z_CMV (three siRNAs per gene) for 35 genes that exhibited a selective decrease (Z‐score < −1) in the TC32‐NR0B1‐luc reporter when silenced. (See Pubchem BioAssay AID: 1159506 and Grohar et al., (2016))

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Schematic depictions of representative transcripts expressed from fusion genes generated by chromosomal rearrangements that disrupt (a) the EML4 and ALK genes (inv(2)(p21p23)). (Adapted from Sabir, Yeoh, Jackson, and Bayliss ()), (b) the BRD4 and NUTM1 genes (t(15;19)(q14;p13)) (Adapted with permission from Thompson‐Wicking et al. (). Copyright 2013 Springer Nature), and (c) the TMPRSS2 and ERG genes (del(21)(q22q22)). Genes and transcripts (not to scale) are shown 5 to 3′. (Adapted with permission from Clark et al. (). Copyright 2007 Springer Nature)

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Schematic depictions of representative transcripts expressed from fusion genes generated by chromosomal rearrangements that disrupt (a) the BCR and ABL genes (t(9;22)(q34;q11)). (Reprinted with permission from Deininger, Goldman, and Melo (). Copyright 2000 American Society of Hematology). (b) The RUNX1 and RUNX1T1 genes (ins(21;20)(q22;q11q11)). Genes and transcripts (not to scale) are shown 5 to 3′. (Adapted with permission from Lam and Zhang ())

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References

Adamo,, P., & Ladomery,, M. R. (2016). The oncogene ERG: A key factor in prostate cancer. Oncogene, 35(4), 403–414. https://doi.org/10.1038/onc.2015.109
Alekseyenko,, A. A., Walsh,, E. M., Wang,, X., Grayson,, A. R., Hsi,, P. T., Kharchenko,, P. V., … French,, C. A. (2015). The oncogenic BRD4‐NUT chromatin regulator drives aberrant transcription within large topological domains. Genes %26 Development, 29(14), 1507–1523. https://doi.org/10.1101/gad.267583.115
Ali,, S. M., Hensing,, T., Schrock,, A. B., Allen,, J., Sanford,, E., Gowen,, K., … Salgia,, R. (2016). Comprehensive genomic profiling identifies a subset of crizotinib‐responsive ALK‐rearranged non‐small cell lung cancer not detected by fluorescence in situ hybridization. The Oncologist, 21(6), 762–770. https://doi.org/10.1634/theoncologist.2015-0497
Baccarani,, M., Castagnetti,, F., Gugliotta,, G., Rosti,, G., Soverini,, S., Albeer,, A., … International BCR‐ABL Study Group. (2019). The proportion of different BCR‐ABL1 transcript types in chronic myeloid leukemia. An international overview. Leukemia, 33, 1173–1183. https://doi.org/10.1038/s41375-018-0341-4
Bailly,, R. A., Bosselut,, R., Zucman,, J., Cormier,, F., Delattre,, O., Roussel,, M., … Ghysdael,, J. (1994). DNA‐binding and transcriptional activation properties of the EWS‐FLI‐1 fusion protein resulting from the t(11;22) translocation in Ewing sarcoma. Molecular and Cellular Biology, 14(5), 3230–3241.
Barnes,, D. J., & Melo,, J. V. (2002). Cytogenetic and molecular genetic aspects of chronic myeloid leukaemia. Acta Haematologica, 108(4), 180–202. https://doi.org/10.1159/000065655
Bauman,, J., Jearawiriyapaisarn,, N., & Kole,, R. (2009). Therapeutic potential of splice‐switching oligonucleotides. Oligonucleotides, 19(1), 1–13. https://doi.org/10.1089/oli.2008.0161
Beghini,, A., Peterlongo,, P., Ripamonti,, C. B., Larizza,, L., Cairoli,, R., Morra,, E., & Mecucci,, C. (2000). C‐kit mutations in core binding factor leukemias. Blood, 95(2), 726–727.
Ben‐Neriah,, Y., Daley,, G. Q., Mes‐Masson,, A. M., Witte,, O. N., & Baltimore,, D. (1986). The chronic myelogenous leukemia‐specific P210 protein is the product of the bcr/abl hybrid gene. Science, 233(4760), 212–214.
Berger,, M., Dirksen,, U., Braeuninger,, A., Koehler,, G., Juergens,, H., Krumbholz,, M., & Metzler,, M. (2013). Genomic EWS‐FLI1 fusion sequences in Ewing sarcoma resemble breakpoint characteristics of immature lymphoid malignancies. PLoS One, 8(2), e56408. https://doi.org/10.1371/journal.pone.0056408
Berget,, S. M. (1995). Exon recognition in vertebrate splicing. Journal of Biological Chemistry, 270(6), 2411–2414.
Berman,, E., Jhanwar,, S., Hedvat,, C., Arcila,, M. E., Wahab,, O. A., Levine,, R., … Albitar,, M. (2016). Resistance to imatinib in patients with chronic myelogenous leukemia and the splice variant BCR‐ABL1(35INS). Leukemia Research, 49, 108–112. https://doi.org/10.1016/j.leukres.2016.08.006
Boland,, J. M., Erdogan,, S., Vasmatzis,, G., Yang,, P., Tillmans,, L. S., Johnson,, M. R., … Yi,, E. S. (2009). Anaplastic lymphoma kinase immunoreactivity correlates with ALK gene rearrangement and transcriptional up‐regulation in non‐small cell lung carcinomas. Human Pathology, 40(8), 1152–1158. https://doi.org/10.1016/j.humpath.2009.01.012
Branford,, S., Rudzki,, Z., & Hughes,, T. P. (2000). A novel BCR‐ABL transcript (e8a2) with the insertion of an inverted sequence of ABL intron 1b in a patient with Philadelphia‐positive chronic myeloid leukaemia. British Journal of Haematology, 109(3), 635–637.
Braun,, B. S., Frieden,, R., Lessnick,, S. L., May,, W. A., & Denny,, C. T. (1995). Identification of target genes for the Ewing`s sarcoma EWS/FLI fusion protein by representational difference analysis. Molecular and Cellular Biology, 15(8), 4623–4630.
Braunschweig,, U., Gueroussov,, S., Plocik,, A. M., Graveley,, B. R., & Blencowe,, B. J. (2013). Dynamic integration of splicing within gene regulatory pathways. Cell, 152(6), 1252–1269. https://doi.org/10.1016/j.cell.2013.02.034
Burnett,, J. C., & Rossi,, J. J. (2012). RNA‐based therapeutics: Current progress and future prospects. Chemistry %26 Biology, 19(1), 60–71. https://doi.org/10.1016/j.chembiol.2011.12.008
Camidge,, D. R., Dziadziuszko,, R., Peters,, S., Mok,, T., Noe,, J., Nowicka,, M., … Shaw,, A. T. (2019). Updated efficacy and safety data and impact of the EML4‐ALK fusion variant on the efficacy of Alectinib in untreated ALK‐positive advanced non‐small‐cell lung cancer in the global phase III ALEX study. Journal of Thoracic Oncology, 14, 1233–1243. https://doi.org/10.1016/j.jtho.2019.03.007
Chan,, L. C., Karhi,, K. K., Rayter,, S. I., Heisterkamp,, N., Eridani,, S., Powles,, R., … Wiedemann,, L. M. (1987). A novel abl protein expressed in Philadelphia chromosome positive acute lymphoblastic leukaemia. Nature, 325(6105), 635–637. https://doi.org/10.1038/325635a0
Choi,, Y. L., Takeuchi,, K., Soda,, M., Inamura,, K., Togashi,, Y., Hatano,, S., … Mano,, H. (2008). Identification of novel isoforms of the EML4‐ALK transforming gene in non‐small cell lung cancer. Cancer Research, 68(13), 4971–4976. https://doi.org/10.1158/0008-5472.CAN-07-6158
Clark,, J., Merson,, S., Jhavar,, S., Flohr,, P., Edwards,, S., Foster,, C. S., … Cooper,, C. S. (2007). Diversity of TMPRSS2‐ERG fusion transcripts in the human prostate. Oncogene, 26(18), 2667–2673. https://doi.org/10.1038/sj.onc.1210070
Connelly,, C. M., Moon,, M. H., & Schneekloth,, J. S., Jr. (2016). The emerging role of RNA as a therapeutic target for small molecules. Cell Chemical Biology, 23(9), 1077–1090. https://doi.org/10.1016/j.chembiol.2016.05.021
COSMIC. (2019). Catalog of somatic mutations in cancer. Retrieved from https://cancer.sanger.ac.uk/cosmic
Costales,, M. G., Suresh,, B., Vishnu,, K., & Disney,, M. D. (2019). Targeted degradation of a hypoxia‐associated non‐coding RNA enhances the selectivity of a small molecule interacting with RNA. Cell Chemical Biology. https://doi.org/10.1016/j.chembiol.2019.04.008
Crompton,, B. D., Stewart,, C., Taylor‐Weiner,, A., Alexe,, G., Kurek,, K. C., Calicchio,, M. L., … Stegmaier,, K. (2014). The genomic landscape of pediatric Ewing sarcoma. Cancer Discovery, 4(11), 1326–1341. https://doi.org/10.1158/2159-8290.CD-13-1037
Crooke,, S. T., Witztum,, J. L., Bennett,, C. F., & Baker,, B. F. (2018). RNA‐targeted therapeutics. Cell Metabolism, 27(4), 714–739. https://doi.org/10.1016/j.cmet.2018.03.004
Cuellar,, S., Vozniak,, M., Rhodes,, J., Forcello,, N., & Olszta,, D. (2018). BCR‐ABL1 tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia. Journal of Oncology Pharmacy Practice, 24(6), 433–452. https://doi.org/10.1177/1078155217710553
Dauphinot,, L., De Oliveira,, C., Melot,, T., Sevenet,, N., Thomas,, V., Weissman,, B. E., & Delattre,, O. (2001). Analysis of the expression of cell cycle regulators in Ewing cell lines: EWS‐FLI‐1 modulates p57KIP2and c‐Myc expression. Oncogene, 20(25), 3258–3265. https://doi.org/10.1038/sj.onc.1204437
De Conti,, L., Baralle,, M., & Buratti,, E. (2013). Exon and intron definition in pre‐mRNA splicing. WIREs RNA, 4(1), 49–60. https://doi.org/10.1002/wrna.1140
de Fabritiis,, P., Petti,, M. C., Montefusco,, E., De Propris,, M. S., Sala,, R., Bellucci,, R., … Mandelli,, F. (1998). BCR‐ABL antisense oligodeoxynucleotide in vitro purging and autologous bone marrow transplantation for patients with chronic myelogenous leukemia in advanced phase. Blood, 91(9), 3156–3162.
Deininger,, M. W., Goldman,, J. M., & Melo,, J. V. (2000). The molecular biology of chronic myeloid leukemia. Blood, 96(10), 3343–3356.
Delattre,, O., Zucman,, J., Plougastel,, B., Desmaze,, C., Melot,, T., Peter,, M., … Thomas,, G. (1992). Gene fusion with an ETS DNA‐binding domain caused by chromosome translocation in human tumours. Nature, 359(6391), 162–165. https://doi.org/10.1038/359162a0
Demehri,, S., Paschka,, P., Schultheis,, B., Lange,, T., Koizumi,, T., Sugimoto,, T., … Deininger,, M. W. (2005). e8a2 BCR‐ABL: More frequent than other atypical BCR‐ABL variants? Leukemia, 19(4), 681–684. https://doi.org/10.1038/sj.leu.2403604
Desmet,, F. O., Hamroun,, D., Lalande,, M., Collod‐Beroud,, G., Claustres,, M., & Beroud,, C. (2009). Human splicing finder: An online bioinformatics tool to predict splicing signals. Nucleic Acids Research, 37(9), e67. https://doi.org/10.1093/nar/gkp215
Dohjima,, T., Lee,, N. S., Li,, H., Ohno,, T., & Rossi,, J. J. (2003). Small interfering RNAs expressed from a Pol III promoter suppress the EWS/Fli‐1 transcript in an Ewing sarcoma cell line. Molecular Therapy, 7(6), 811–816.
Dominguez,, D., Freese,, P., Alexis,, M. S., Su,, A., Hochman,, M., Palden,, T., … Burge,, C. B. (2018). Sequence, structure, and context preferences of human RNA binding proteins. Molecular Cell, 70(5), 854–867.e859. https://doi.org/10.1016/j.molcel.2018.05.001
Druker,, B. J., Talpaz,, M., Resta,, D. J., Peng,, B., Buchdunger,, E., Ford,, J. M., … Sawyers,, C. L. (2001). Efficacy and safety of a specific inhibitor of the BCR‐ABL tyrosine kinase in chronic myeloid leukemia. The New England Journal of Medicine, 344(14), 1031–1037. https://doi.org/10.1056/NEJM200104053441401
Era,, T., Asou,, N., Kunisada,, T., Yamasaki,, H., Asou,, H., Kamada,, N., … Takatsuki,, K. (1995). Identification of two transcripts of AML1/ETO‐fused gene in t(8;21) leukemic cells and expression of wild‐type ETO gene in hematopoietic cells. Genes, Chromosomes %26 Cancer, 13(1), 25–33.
Erickson,, P., Gao,, J., Chang,, K. S., Look,, T., Whisenant,, E., Raimondi,, S., … Drabkin,, H. (1992). Identification of breakpoints in t(8;21) acute myelogenous leukemia and isolation of a fusion transcript, AML1/ETO, with similarity to Drosophila segmentation gene, runt. Blood, 80(7), 1825–1831.
Evers,, M. M., Toonen,, L. J., & van Roon‐Mom,, W. M. (2015). Antisense oligonucleotides in therapy for neurodegenerative disorders. Advanced Drug Delivery Reviews, 87, 90–103. https://doi.org/10.1016/j.addr.2015.03.008
French,, C. A. (2012). Pathogenesis of NUT midline carcinoma. Annual Review of Pathology, 7, 247–265. https://doi.org/10.1146/annurev-pathol-011811-132438
French,, C. A. (2018). NUT carcinoma: Clinicopathologic features, pathogenesis, and treatment. Pathology International, 68(11), 583–595. https://doi.org/10.1111/pin.12727
French,, C. A., Miyoshi,, I., Kubonishi,, I., Grier,, H. E., Perez‐Atayde,, A. R., & Fletcher,, J. A. (2003). BRD4‐NUT fusion oncogene: A novel mechanism in aggressive carcinoma. Cancer Research, 63(2), 304–307.
French,, C. A., Ramirez,, C. L., Kolmakova,, J., Hickman,, T. T., Cameron,, M. J., Thyne,, M. E., … Aster,, J. C. (2008). BRD‐NUT oncoproteins: A family of closely related nuclear proteins that block epithelial differentiation and maintain the growth of carcinoma cells. Oncogene, 27(15), 2237–2242. https://doi.org/10.1038/sj.onc.1210852
Gao,, Q., Liang,, W. W., Foltz,, S. M., Mutharasu,, G., Jayasinghe,, R. G., Cao,, S., … Ding,, L. (2018). Driver fusions and their implications in the development and treatment of human cancers. Cell Reports, 23(1), 227–238.e223. https://doi.org/10.1016/j.celrep.2018.03.050
Geuens,, T., Bouhy,, D., & Timmerman,, V. (2016). The hnRNP family: Insights into their role in health and disease. Human Genetics, 135(8), 851–867. https://doi.org/10.1007/s00439-016-1683-5
Gianfelici,, V., Lahortiga,, I., & Cools,, J. (2012). Chromosomal aberrations and fusion genes in myeloid malignancies. Expert Review of Hematology, 5(4), 381–393. https://doi.org/10.1586/ehm.12.30
Gorohovski,, A., Tagore,, S., Palande,, V., Malka,, A., Raviv‐Shay,, D., & Frenkel‐Morgenstern,, M. (2017). ChiTaRS‐3.1‐the enhanced chimeric transcripts and RNA‐seq database matched with protein–protein interactions. Nucleic Acids Research, 45(D1), D790–D795. https://doi.org/10.1093/nar/gkw1127
Gough,, S. M., Slape,, C. I., & Aplan,, P. D. (2011). NUP98 gene fusions and hematopoietic malignancies: Common themes and new biologic insights. Blood, 118(24), 6247–6257. https://doi.org/10.1182/blood-2011-07-328880
Grinev,, V. V., Migas,, A. A., Kirsanava,, A. D., Mishkova,, O. A., Siomava,, N., Ramanouskaya,, T. V., … Aleinikova,, O. V. (2015). Decoding of exon splicing patterns in the human RUNX1‐RUNX1T1 fusion gene. The International Journal of Biochemistry %26 Cell Biology, 68, 48–58. https://doi.org/10.1016/j.biocel.2015.08.017
Grohar,, P. J., Kim,, S., Rangel Rivera,, G. O., Sen,, N., Haddock,, S., Harlow,, M. L., … Caplen,, N. J. (2016). Functional genomic screening reveals splicing of the EWS‐FLI1 fusion transcript as a vulnerability in Ewing sarcoma. Cell Reports, 14(3), 598–610. https://doi.org/10.1016/j.celrep.2015.12.063
Gruber,, F. X., Lundan,, T., Goll,, R., Silye,, A., Mikkola,, I., Rekvig,, O. P., … Hjorth‐Hansen,, H. (2012). BCR‐ABL isoforms associated with intrinsic or acquired resistance to imatinib: More heterogeneous than just ABL kinase domain point mutations? Medical Oncology, 29(1), 219–226. https://doi.org/10.1007/s12032-010-9781-z
Hagen,, R. M., Adamo,, P., Karamat,, S., Oxley,, J., Aning,, J. J., Gillatt,, D., … Rhodes,, A. (2014). Quantitative analysis of ERG expression and its splice isoforms in formalin‐fixed, paraffin‐embedded prostate cancer samples: Association with seminal vesicle invasion and biochemical recurrence. American Journal of Clinical Pathology, 142(4), 533–540. https://doi.org/10.1309/AJCPH88QHXARISUP
Hahm,, K. B., Cho,, K., Lee,, C., Im,, Y. H., Chang,, J., Choi,, S. G., … Kim,, S. J. (1999). Repression of the gene encoding the TGF‐beta type II receptor is a major target of the EWS‐FLI1 oncoprotein. Nature Genetics, 23(2), 222–227. https://doi.org/10.1038/13854
Hatlen,, M. A., Wang,, L., & Nimer,, S. D. (2012). AML1‐ETO driven acute leukemia: Insights into pathogenesis and potential therapeutic approaches. Frontiers in Medicine, 6(3), 248–262. https://doi.org/10.1007/s11684-012-0206-6
Havens,, M. A., & Hastings,, M. L. (2016). Splice‐switching antisense oligonucleotides as therapeutic drugs. Nucleic Acids Research, 44(14), 6549–6563. https://doi.org/10.1093/nar/gkw533
Hawkins,, D. S., Bölling,, T., Dubois,, S., Hogendoorn,, P. C. W., Jürgens,, H., Paulussen,, M., … Lessnick,, S. L. (2011). Ewing sarcoma. In P. A. Pizzo, & D. G. Poplack, (Eds.), Principles and practice of pediatric oncology (6th ed.). Philadelphia, PA: Lippincott Williams %26 Wilkins.
Heuckmann,, J. M., Balke‐Want,, H., Malchers,, F., Peifer,, M., Sos,, M. L., Koker,, M., … Thomas,, R. K. (2012). Differential protein stability and ALK inhibitor sensitivity of EML4‐ALK fusion variants. Clinical Cancer Research, 18(17), 4682–4690. https://doi.org/10.1158/1078-0432.CCR-11-3260
Heyer,, E. E., Deveson,, I. W., Wooi,, D., Selinger,, C. I., Lyons,, R. J., Hayes,, V. M., … Blackburn,, J. (2019). Diagnosis of fusion genes using targeted RNA sequencing. Nature Communications, 10(1), 1388. https://doi.org/10.1038/s41467-019-09374-9
Higuchi,, M., O`Brien,, D., Kumaravelu,, P., Lenny,, N., Yeoh,, E. J., & Downing,, J. R. (2002). Expression of a conditional AML1‐ETO oncogene bypasses embryonic lethality and establishes a murine model of human t(8;21) acute myeloid leukemia. Cancer Cell, 1(1), 63–74.
Hochhaus,, A., Reiter,, A., Skladny,, H., Melo,, J. V., Sick,, C., Berger,, U., … Cross,, N. C. (1996). A novel BCR‐ABL fusion gene (e6a2) in a patient with Philadelphia chromosome‐negative chronic myelogenous leukemia. Blood, 88(6), 2236–2240.
Holla,, V. R., Elamin,, Y. Y., Bailey,, A. M., Johnson,, A. M., Litzenburger,, B. C., Khotskaya,, Y. B., … Simon,, G. R. (2017). ALK: A tyrosine kinase target for cancer therapy. Cold Spring Harbor Molecular Case Studies, 3(1), a001115. https://doi.org/10.1101/mcs.a001115
Hu,, Y., Dobi,, A., Sreenath,, T., Cook,, C., Tadase,, A. Y., Ravindranath,, L., … Srivastava,, S. (2008). Delineation of TMPRSS2‐ERG splice variants in prostate cancer. Clinical Cancer Research, 14(15), 4719–4725. https://doi.org/10.1158/1078-0432.CCR-08-0531
Irimia,, M., & Blencowe,, B. J. (2012). Alternative splicing: Decoding an expansive regulatory layer. Current Opinion in Cell Biology, 24(3), 323–332. https://doi.org/10.1016/j.ceb.2012.03.005
Jividen,, K., & Li,, H. (2014). Chimeric RNAs generated by intergenic splicing in normal and cancer cells. Genes, Chromosomes %26 Cancer, 53(12), 963–971. https://doi.org/10.1002/gcc.22207
Johansson,, B., Mertens,, F., Schyman,, T., Bjork,, J., Mandahl,, N., & Mitelman,, F. (2019). Most gene fusions in cancer are stochastic events. Genes, Chromosomes %26 Cancer, 58(9), 607–611. https://doi.org/10.1002/gcc.22745
Jumbe,, S. L., Porazinski,, S. R., Oltean,, S., Mansell,, J. P., Vahabi,, B., Wilson,, I. D., & Ladomery,, M. R. (2019). The evolutionarily conserved cassette exon 7b drives ERG`s oncogenic properties. Translational Oncology, 12(1), 134–142. https://doi.org/10.1016/j.tranon.2018.09.001
Jurica,, M. S., & Moore,, M. J. (2003). Pre‐mRNA splicing: Awash in a sea of proteins. Molecular Cell, 12(1), 5–14.
Keren,, H., Lev‐Maor,, G., & Ast,, G. (2010). Alternative splicing and evolution: Diversification, exon definition and function. Nature Reviews. Genetics, 11(5), 345–355. https://doi.org/10.1038/nrg2776
Koldehoff,, M., Steckel,, N. K., Beelen,, D. W., & Elmaagacli,, A. H. (2007). Therapeutic application of small interfering RNA directed against bcr‐abl transcripts to a patient with imatinib‐resistant chronic myeloid leukaemia. Clinical and Experimental Medicine, 7(2), 47–55. https://doi.org/10.1007/s10238-007-0125-z
Kozu,, T., Fukuyama,, T., Yamami,, T., Akagi,, K., & Kaneko,, Y. (2005). MYND‐less splice variants of AML1‐MTG8 (RUNX1‐CBFA2T1) are expressed in leukemia with t(8;21). Genes, Chromosomes %26 Cancer, 43(1), 45–53. https://doi.org/10.1002/gcc.20165
Kozu,, T., Miyoshi,, H., Shimizu,, K., Maseki,, N., Kaneko,, Y., Asou,, H., … Ohki,, M. (1993). Junctions of the AML1/MTG8(ETO) fusion are constant in t(8;21) acute myeloid leukemia detected by reverse transcription polymerase chain reaction. Blood, 82(4), 1270–1276.
Kumar,, S., Razzaq,, S. K., Vo,, A. D., Gautam,, M., & Li,, H. (2016). Identifying fusion transcripts using next generation sequencing. WIREs RNA, 7(6), 811–823. https://doi.org/10.1002/wrna.1382
Kumar‐Sinha,, C., Kalyana‐Sundaram,, S., & Chinnaiyan,, A. M. (2015). Landscape of gene fusions in epithelial cancers: seq and ye shall find. Genome Medicine, 7, 129. https://doi.org/10.1186/s13073-015-0252-1
Kumar‐Sinha,, C., Tomlins,, S. A., & Chinnaiyan,, A. M. (2008). Recurrent gene fusions in prostate cancer. Nature Reviews. Cancer, 8(7), 497–511. https://doi.org/10.1038/nrc2402
Kurzrock,, R., Gutterman,, J. U., & Talpaz,, M. (1988). The molecular genetics of Philadelphia chromosome‐positive leukemias. The New England Journal of Medicine, 319(15), 990–998. https://doi.org/10.1056/NEJM198810133191506
Kwak,, E. L., Bang,, Y. J., Camidge,, D. R., Shaw,, A. T., Solomon,, B., Maki,, R. G., … Iafrate,, A. J. (2010). Anaplastic lymphoma kinase inhibition in non‐small‐cell lung cancer. The New England Journal of Medicine, 363(18), 1693–1703. https://doi.org/10.1056/NEJMoa1006448
LaFiura,, K. M., Edwards,, H., Taub,, J. W., Matherly,, L. H., Fontana,, J. A., Mohamed,, A. N., … Children`s Oncology Group. (2008). Identification and characterization of novel AML1‐ETO fusion transcripts in pediatric t(8;21) acute myeloid leukemia: A report from the Children`s Oncology Group. Oncogene, 27(36), 4933–4942. https://doi.org/10.1038/onc.2008.134
Lam,, K., & Zhang,, D. E. (2012). RUNX1 and RUNX1‐ETO: Roles in hematopoiesis and leukemogenesis. Frontiers in Bioscience (Landmark Edition), 17, 1120–1139.
Laudadio,, J., Deininger,, M. W., Mauro,, M. J., Druker,, B. J., & Press,, R. D. (2008). An intron‐derived insertion/truncation mutation in the BCR‐ABL kinase domain in chronic myeloid leukemia patients undergoing kinase inhibitor therapy. Journal of Molecular Diagnostics, 10(2), 177–180. https://doi.org/10.2353/jmoldx.2008.070128
Lee,, T. S., Ma,, W., Zhang,, X., Giles,, F., Cortes,, J., Kantarjian,, H., & Albitar,, M. (2008). BCR‐ABL alternative splicing as a common mechanism for imatinib resistance: Evidence from molecular dynamics simulations. Molecular Cancer Therapeutics, 7(12), 3834–3841. https://doi.org/10.1158/1535-7163.MCT-08-0482
Li,, H., Wang,, J., Ma,, X., & Sklar,, J. (2009). Gene fusions and RNA trans‐splicing in normal and neoplastic human cells. Cell Cycle, 8(2), 218–222. https://doi.org/10.4161/cc.8.2.7358
Li,, S., Ilaria,, R. L., Jr., Million,, R. P., Daley,, G. Q., & Van Etten,, R. A. (1999). The P190, P210, and P230 forms of the BCR/ABL oncogene induce a similar chronic myeloid leukemia‐like syndrome in mice but have different lymphoid leukemogenic activity. Journal of Experimental Medicine, 189(9), 1399–1412.
Lieberman,, J. (2018). Tapping the RNA world for therapeutics. Nature Structural %26 Molecular Biology, 25(5), 357–364. https://doi.org/10.1038/s41594-018-0054-4
Lin,, J. J., Zhu,, V. W., Yoda,, S., Yeap,, B. Y., Schrock,, A. B., Dagogo‐Jack,, I., … Ou,, S. I. (2018). Impact of EML4‐ALK variant on resistance mechanisms and clinical outcomes in ALK‐positive lung cancer. Journal of Clinical Oncology, 36(12), 1199–1206. https://doi.org/10.1200/JCO.2017.76.2294
Ma,, W., Kantarjian,, H., Yeh,, C. H., Zhang,, Z. J., Cortes,, J., & Albitar,, M. (2009). BCR‐ABL truncation due to premature translation termination as a mechanism of resistance to kinase inhibitors. Acta Haematologica, 121(1), 27–31. https://doi.org/10.1159/000210060
Mannari,, D., Gascoyne,, D., Dunne,, J., Chaplin,, T., & Young,, B. (2010). A novel exon in AML1‐ETO negatively influences the clonogenic potential of the t(8;21) in acute myeloid leukemia. Leukemia, 24(4), 891–894. https://doi.org/10.1038/leu.2009.288
Marin,, D., Milojkovic,, D., Olavarria,, E., Khorashad,, J. S., de Lavallade,, H., Reid,, A. G., … Apperley,, J. F. (2008). European LeukemiaNet criteria for failure or suboptimal response reliably identify patients with CML in early chronic phase treated with imatinib whose eventual outcome is poor. Blood, 112(12), 4437–4444. https://doi.org/10.1182/blood-2008-06-162388
Matissek,, K. J., Onozato,, M. L., Sun,, S., Zheng,, Z., Schultz,, A., Lee,, J., … Ellisen,, L. W. (2018). Expressed gene fusions as frequent drivers of poor outcomes in hormone receptor‐positive breast cancer. Cancer Discovery, 8(3), 336–353. https://doi.org/10.1158/2159-8290.CD-17-0535
May,, W. A., Gishizky,, M. L., Lessnick,, S. L., Lunsford,, L. B., Lewis,, B. C., Delattre,, O., … Denny,, C. T. (1993). Ewing sarcoma 11;22 translocation produces a chimeric transcription factor that requires the DNA‐binding domain encoded by FLI1 for transformation. Proceedings of the National Academy of Sciences of the United States of America, 90(12), 5752–5756.
Melo,, J. V. (1996). The diversity of BCR‐ABL fusion proteins and their relationship to leukemia phenotype. Blood, 88(7), 2375–2384.
Mertens,, F., Antonescu,, C. R., & Mitelman,, F. (2016). Gene fusions in soft tissue tumors: Recurrent and overlapping pathogenetic themes. Genes, Chromosomes %26 Cancer, 55(4), 291–310. https://doi.org/10.1002/gcc.22335
Mertens,, F., Johansson,, B., Fioretos,, T., & Mitelman,, F. (2015). The emerging complexity of gene fusions in cancer. Nature Reviews. Cancer, 15(6), 371–381. https://doi.org/10.1038/nrc3947
Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer. (2019). In F. Mitelman, B. Johansson & F. Mertens (Eds.). Retrieved from http://cgap.nci.nih.gov/Chromosomes/Mitelman
Mitelman,, F., Johansson,, B., & Mertens,, F. (2007). The impact of translocations and gene fusions on cancer causation. Nature Reviews. Cancer, 7(4), 233–245. https://doi.org/10.1038/nrc2091
Muller,, A. M., Duque,, J., Shizuru,, J. A., & Lubbert,, M. (2008). Complementing mutations in core binding factor leukemias: From mouse models to clinical applications. Oncogene, 27(44), 5759–5773. https://doi.org/10.1038/onc.2008.196
Nagano,, A., Ohno,, T., Shimizu,, K., Hara,, A., Yamamoto,, T., Kawai,, G., … Takei,, Y. (2010). EWS/Fli‐1 chimeric fusion gene upregulates vascular endothelial growth factor‐A. International Journal of Cancer, 126(12), 2790–2798. https://doi.org/10.1002/ijc.24781
Nilsen,, T. W., & Graveley,, B. R. (2010). Expansion of the eukaryotic proteome by alternative splicing. Nature, 463(7280), 457–463. https://doi.org/10.1038/nature08909
O`Hare,, T., Zabriskie,, M. S., Eide,, C. A., Agarwal,, A., Adrian,, L. T., You,, H., … Druker,, B. J. (2011). The BCR‐ABL35INS insertion/truncation mutant is kinase‐inactive and does not contribute to tyrosine kinase inhibitor resistance in chronic myeloid leukemia. Blood, 118(19), 5250–5254. https://doi.org/10.1182/blood-2011-05-349191
Pan,, Q., Shai,, O., Lee,, L. J., Frey,, B. J., & Blencowe,, B. J. (2008). Deep surveying of alternative splicing complexity in the human transcriptome by high‐throughput sequencing. Nature Genetics, 40(12), 1413–1415. https://doi.org/10.1038/ng.259
Patocs,, B., Nemeth,, K., Garami,, M., Arato,, G., Kovalszky,, I., Szendroi,, M., & Fekete,, G. (2013). Multiple splice variants of EWSR1‐ETS fusion transcripts co‐existing in the Ewing sarcoma family of tumors. Cellular Oncology (Dordrecht), 36(3), 191–200. https://doi.org/10.1007/s13402-013-0126-8
Perner,, S., Demichelis,, F., Beroukhim,, R., Schmidt,, F. H., Mosquera,, J. M., Setlur,, S., … Rubin,, M. A. (2006). TMPRSS2:ERG fusion‐associated deletions provide insight into the heterogeneity of prostate cancer. Cancer Research, 66(17), 8337–8341. https://doi.org/10.1158/0008-5472.CAN-06-1482
Poirier,, A., Weetall,, M., Heinig,, K., Bucheli,, F., Schoenlein,, K., Alsenz,, J., … Mueller,, L. (2018). Risdiplam distributes and increases SMN protein in both the central nervous system and peripheral organs. Pharmacology Research %26 Perspectives, 6(6), e00447. https://doi.org/10.1002/prp2.447
Ratni,, H., Ebeling,, M., Baird,, J., Bendels,, S., Bylund,, J., Chen,, K. S., … Mueller,, L. (2018). Discovery of Risdiplam, a Selective Survival of Motor Neuron‐2 (SMN2) gene splicing modifier for the treatment of spinal muscular atrophy (SMA). Journal of Medicinal Chemistry, 61(15), 6501–6517. https://doi.org/10.1021/acs.jmedchem.8b00741
Reynoird,, N., Schwartz,, B. E., Delvecchio,, M., Sadoul,, K., Meyers,, D., Mukherjee,, C., … Khochbin,, S. (2010). Oncogenesis by sequestration of CBP/p300 in transcriptionally inactive hyperacetylated chromatin domains. The EMBO Journal, 29(17), 2943–2952. https://doi.org/10.1038/emboj.2010.176
Rikova,, K., Guo,, A., Zeng,, Q., Possemato,, A., Yu,, J., Haack,, H., … Comb,, M. J. (2007). Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell, 131(6), 1190–1203. https://doi.org/10.1016/j.cell.2007.11.025
Roberts,, K. G., & Mullighan,, C. G. (2015). Genomics in acute lymphoblastic leukaemia: Insights and treatment implications. Nature Reviews. Clinical Oncology, 12(6), 344–357. https://doi.org/10.1038/nrclinonc.2015.38
Rossari,, F., Minutolo,, F., & Orciuolo,, E. (2018). Past, present, and future of Bcr‐Abl inhibitors: From chemical development to clinical efficacy. Journal of Hematology %26 Oncology, 11(1), 84. https://doi.org/10.1186/s13045-018-0624-2
Rowley,, J. D. (1984). Biological implications of consistent chromosome rearrangements in leukemia and lymphoma. Cancer Research, 44(8), 3159–3168.
Sabir,, S. R., Yeoh,, S., Jackson,, G., & Bayliss,, R. (2017). EML4‐ALK variants: Biological and molecular properties, and the implications for patients. Cancers (Basel), 9(9) pii: E118. https://doi.org/10.3390/cancers9090118
Saglio,, G., Pane,, F., Gottardi,, E., Frigeri,, F., Buonaiuto,, M. R., Guerrasio,, A., … Salvatore,, F. (1996). Consistent amounts of acute leukemia‐associated P190BCR/ABL transcripts are expressed by chronic myelogenous leukemia patients at diagnosis. Blood, 87(3), 1075–1080.
Saleh,, A. F., Arzumanov,, A. A., & Gait,, M. J. (2012). Overview of alternative oligonucleotide chemistries for exon skipping. Methods in Molecular Biology, 867, 365–378. https://doi.org/10.1007/978-1-61779-767-5_23
Sankar,, S., & Lessnick,, S. L. (2011). Promiscuous partnerships in Ewing`s sarcoma. Cancer Genetics, 204(7), 351–365. https://doi.org/10.1016/j.cancergen.2011.07.008
Sasaki,, T., Rodig,, S. J., Chirieac,, L. R., & Janne,, P. A. (2010). The biology and treatment of EML4‐ALK non‐small cell lung cancer. European Journal of Cancer, 46(10), 1773–1780. https://doi.org/10.1016/j.ejca.2010.04.002
Setten,, R. L., Rossi,, J. J., & Han,, S. P. (2019). The current state and future directions of RNAi‐based therapeutics. Nature Reviews Drug Discovery, 18(6), 421–446. https://doi.org/10.1038/s41573-019-0017-4
Shah,, R. B., & Chinnaiyan,, A. M. (2009). The discovery of common recurrent transmembrane protease serine 2 (TMPRSS2)‐erythroblastosis virus E26 transforming sequence (ETS) gene fusions in prostate cancer: Significance and clinical implications. Advances in Anatomic Pathology, 16(3), 145–153. https://doi.org/10.1097/PAP.0b013e3181a12da7
Sharma,, V. K., & Watts,, J. K. (2015). Oligonucleotide therapeutics: Chemistry, delivery and clinical progress. Future Medicinal Chemistry, 7(16), 2221–2242. https://doi.org/10.4155/fmc.15.144
Shaw,, A. T., Yeap,, B. Y., Mino‐Kenudson,, M., Digumarthy,, S. R., Costa,, D. B., Heist,, R. S., … Iafrate,, A. J. (2009). Clinical features and outcome of patients with non‐small‐cell lung cancer who harbor EML4‐ALK. Journal of Clinical Oncology, 27(26), 4247–4253. https://doi.org/10.1200/JCO.2009.22.6993
Shi,, Y. (2017). Mechanistic insights into precursor messenger RNA splicing by the spliceosome. Nature Reviews. Molecular Cell Biology, 18(11), 655–670. https://doi.org/10.1038/nrm.2017.86
Shtivelman,, E., Lifshitz,, B., Gale,, R. P., Roe,, B. A., & Canaani,, E. (1986). Alternative splicing of RNAs transcribed from the human abl gene and from the bcr‐abl fused gene. Cell, 47(2), 277–284.
Skorski,, T., Nieborowska‐Skorska,, M., Nicolaides,, N. C., Szczylik,, C., Iversen,, P., Iozzo,, R. V., … Calabretta,, B. (1994). Suppression of Philadelphia1 leukemia cell growth in mice by BCR‐ABL antisense oligodeoxynucleotide. Proceedings of the National Academy of Sciences of the United States of America, 91(10), 4504–4508. https://doi.org/10.1073/pnas.91.10.4504
Soda,, M., Choi,, Y. L., Enomoto,, M., Takada,, S., Yamashita,, Y., Ishikawa,, S., … Mano,, H. (2007). Identification of the transforming EML4‐ALK fusion gene in non‐small‐cell lung cancer. Nature, 448(7153), 561–566. https://doi.org/10.1038/nature05945
Soldevilla,, M. M., Meraviglia‐Crivelli de Caso,, D., Menon,, A. P., & Pastor,, F. (2018). Aptamer‐iRNAs as therapeutics for cancer treatment. Pharmaceuticals (Basel), 11(4) pii: E108. https://doi.org/10.3390/ph11040108
Sorensen,, P. H., Lessnick,, S. L., Lopez‐Terrada,, D., Liu,, X. F., Triche,, T. J., & Denny,, C. T. (1994). A second Ewing`s sarcoma translocation, t(21;22), fuses the EWS gene to another ETS‐family transcription factor, ERG. Nature Genetics, 6(2), 146–151. https://doi.org/10.1038/ng0294-146
Sperling,, R. (2017). The nuts and bolts of the endogenous spliceosome. WIREs RNA, 8(1). https://doi.org/10.1002/wrna.1377
Sturm,, S., Gunther,, A., Jaber,, B., Jordan,, P., Al Kotbi,, N., Parkar,, N., … Khwaja,, O. (2019). A phase 1 healthy male volunteer single escalating dose study of the pharmacokinetics and pharmacodynamics of risdiplam (RG7916, RO7034067), a SMN2 splicing modifier. British Journal of Clinical Pharmacology, 85(1), 181–193. https://doi.org/10.1111/bcp.13786
Takeuchi,, K., Choi,, Y. L., Soda,, M., Inamura,, K., Togashi,, Y., Hatano,, S., … Mano,, H. (2008). Multiplex reverse transcription‐PCR screening for EML4‐ALK fusion transcripts. Clinical Cancer Research, 14(20), 6618–6624. https://doi.org/10.1158/1078-0432.CCR-08-1018
Talpaz,, M., Shah,, N. P., Kantarjian,, H., Donato,, N., Nicoll,, J., Paquette,, R., … Sawyers,, C. L. (2006). Dasatinib in imatinib‐resistant Philadelphia chromosome‐positive leukemias. The New England Journal of Medicine, 354(24), 2531–2541. https://doi.org/10.1056/NEJMoa055229
Thomas,, X., & Heiblig,, M. (2016). The development of agents targeting the BCR‐ABL tyrosine kinase as Philadelphia chromosome‐positive acute lymphoblastic leukemia treatment. Expert Opinion on Drug Discovery, 11(11), 1061–1070. https://doi.org/10.1080/17460441.2016.1227318
Thompson‐Wicking,, K., Francis,, R. W., Stirnweiss,, A., Ferrari,, E., Welch,, M. D., Baker,, E., … Beesley,, A. H. (2013). Novel BRD4‐NUT fusion isoforms increase the pathogenic complexity in NUT midline carcinoma. Oncogene, 32(39), 4664–4674. https://doi.org/10.1038/onc.2012.487
Tomlins,, S. A., Rhodes,, D. R., Perner,, S., Dhanasekaran,, S. M., Mehra,, R., Sun,, X. W., … Chinnaiyan,, A. M. (2005). Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science, 310(5748), 644–648. https://doi.org/10.1126/science.1117679
Varley,, K. E., Gertz,, J., Roberts,, B. S., Davis,, N. S., Bowling,, K. M., Kirby,, M. K., … Myers,, R. M. (2014). Recurrent read‐through fusion transcripts in breast cancer. Breast Cancer Research and Treatment, 146(2), 287–297. https://doi.org/10.1007/s10549-014-3019-2
Wang,, J., Cai,, Y., Yu,, W., Ren,, C., Spencer,, D. M., & Ittmann,, M. (2008). Pleiotropic biological activities of alternatively spliced TMPRSS2/ERG fusion gene transcripts. Cancer Research, 68(20), 8516–8524. https://doi.org/10.1158/0008-5472.CAN-08-1147
Wang,, J., Schultz,, P. G., & Johnson,, K. A. (2018). Mechanistic studies of a small‐molecule modulator of SMN2 splicing. Proceedings of the National Academy of Sciences of the United States of America, 115(20), E4604–E4612. https://doi.org/10.1073/pnas.1800260115
Wang,, R., & You,, J. (2015). Mechanistic analysis of the role of bromodomain‐containing protein 4 (BRD4) in BRD4‐NUT oncoprotein‐induced transcriptional activation. Journal of Biological Chemistry, 290(5), 2744–2758. https://doi.org/10.1074/jbc.M114.600759
Weerkamp,, F., Dekking,, E., Ng,, Y. Y., van der Velden,, V. H., Wai,, H., Bottcher,, S., … EuroFlow,, C. (2009). Flow cytometric immunobead assay for the detection of BCR‐ABL fusion proteins in leukemia patients. Leukemia, 23(6), 1106–1117. https://doi.org/10.1038/leu.2009.93
White,, D. L., Dang,, P., Engler,, J., Frede,, A., Zrim,, S., Osborn,, M., … Hughes,, T. P. (2010). Functional activity of the OCT‐1 protein is predictive of long‐term outcome in patients with chronic‐phase chronic myeloid leukemia treated with imatinib. Journal of Clinical Oncology, 28(16), 2761–2767. https://doi.org/10.1200/JCO.2009.26.5819
White,, D. L., Saunders,, V. A., Dang,, P., Engler,, J., Zannettino,, A. C., Cambareri,, A. C., … Hughes,, T. P. (2006). OCT‐1‐mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): Reduced OCT‐1 activity is the cause of low in vitro sensitivity to imatinib. Blood, 108(2), 697–704. https://doi.org/10.1182/blood-2005-11-4687
Woo,, C. G., Seo,, S., Kim,, S. W., Jang,, S. J., Park,, K. S., Song,, J. Y., … Choi,, J. (2017). Differential protein stability and clinical responses of EML4‐ALK fusion variants to various ALK inhibitors in advanced ALK‐rearranged non‐small cell lung cancer. Annals of Oncology, 28(4), 791–797. https://doi.org/10.1093/annonc/mdw693
Wright,, R. L., & Vaughan,, A. T. (2014). A systematic description of MLL fusion gene formation. Critical Reviews in Oncology/Hematology, 91(3), 283–291. https://doi.org/10.1016/j.critrevonc.2014.03.004
Yan,, J., Diaz,, J., Jiao,, J., Wang,, R., & You,, J. (2011). Perturbation of BRD4 protein function by BRD4‐NUT protein abrogates cellular differentiation in NUT midline carcinoma. Journal of Biological Chemistry, 286(31), 27663–27675. https://doi.org/10.1074/jbc.M111.246975
Yan,, M., Kanbe,, E., Peterson,, L. F., Boyapati,, A., Miao,, Y., Wang,, Y., … Zhang,, D. E. (2006). A previously unidentified alternatively spliced isoform of t(8;21) transcript promotes leukemogenesis. Nature Medicine, 12(8), 945–949. https://doi.org/10.1038/nm1443
Yoshida,, T., Oya,, Y., Tanaka,, K., Shimizu,, J., Horio,, Y., Kuroda,, H., … Yatabe,, Y. (2016). Differential crizotinib response duration among ALK fusion variants in ALK‐positive non‐small‐cell lung cancer. Journal of Clinical Oncology, 34(28), 3383–3389. https://doi.org/10.1200/JCO.2015.65.8732
Yuan,, Y., Zhou,, L., Miyamoto,, T., Iwasaki,, H., Harakawa,, N., Hetherington,, C. J., … Zhang,, D. E. (2001). AML1‐ETO expression is directly involved in the development of acute myeloid leukemia in the presence of additional mutations. Proceedings of the National Academy of Sciences of the United States of America, 98(18), 10398–10403. https://doi.org/10.1073/pnas.171321298
Zhang,, Y., Gong,, M., Yuan,, H., Park,, H. G., Frierson,, H. F., & Li,, H. (2012). Chimeric transcript generated by cis‐splicing of adjacent genes regulates prostate cancer cell proliferation. Cancer Discovery, 2(7), 598–607. https://doi.org/10.1158/2159-8290.CD-12-0042
Zhu,, L., Zhang,, Y., Zhang,, W., Yang,, S., Chen,, J. Q., & Tian,, D. (2009). Patterns of exon–intron architecture variation of genes in eukaryotic genomes. BMC Genomics, 10, 47. https://doi.org/10.1186/1471-2164-10-47
Zoubek,, A., Pfleiderer,, C., Salzer‐Kuntschik,, M., Amann,, G., Windhager,, R., Fink,, F. M., … Kovar,, H. (1994). Variability of EWS chimaeric transcripts in Ewing tumours: A comparison of clinical and molecular data. British Journal of Cancer, 70(5), 908–913.
Zucman,, J., Melot,, T., Desmaze,, C., Ghysdael,, J., Plougastel,, B., Peter,, M., … Turc‐Carel,, C. (1993). Combinatorial generation of variable fusion proteins in the Ewing family of tumours. The EMBO Journal, 12(12), 4481–4487.

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