Bradley Lab

RNA splicing dysregulation and the hallmarks of cancer
Bradley RK^†, Anczuków O^†
Nature Reviews Cancer https://doi.org/10.1038/s41568-022-00541-7 (2023) ^†co-corresponding authors

Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia
Wang E*^,†, Pineda JMB*, Kim WJ*, Chen S, Bourcier J, Stahl M, Hogg SJ, Bewersdorf JP, Han C, Singer ME, Cui D, Erickson CE, Tittley SM, Penson AV, Knorr K, Stanley RF, Rahman J, Krishnamoorthy G, Fagin JA, Creger E, McMillan E, Mak C-C, Jarvis M, Bossard C, Beaupre DM, Bradley RK^†, Abdel-Wahab O^†
Cancer Cell 41:1-17 (2022) *co-first authors; ^†co-corresponding authors

Featured in Cancer Discovery.

Activation of targetable inflammatory immune signaling is seen in myelodysplastic syndromes with SF3B1 mutations
Choudhary GS, Pellagatti A, Agianian B, Smith MA, Bhagat TD, Gordon-Mitchell S, Sahu S, Pandey S, Shah N, Aluri S, Aggarwal R, Aminov S, Schwartz L, Steeples V, Booher RN, Ramachandra M, Samson M, Carbajal M, Pradhan K, Bowman TV, Pillai MM, Will B, Wickrema A, Shastri A, Bradley RK, Martell RE, Steidl RG, Gavathiotis E, Boultwood J, Starczynowski DT, Verma A
eLife 11:e78136 (2022)

Synthetic introns enable splicing factor mutation-dependent targeting of cancer cells
North K*, Benbarche S*, Liu B, Pangallo J, Chen S, Stahl M, Bewersdorf JP, Stanley RF, Erickson C, Cho H, Pineda JMB, Thomas JD, Polaski JT, Belleville AE, Gabel AM, Udy DB, Humbert O, Kiem H-P, Abdel-Wahab O^†, Bradley RK^†
Nature Biotechnology 40:1103–1113 (2022) *co-first authors; ^†co-corresponding authors

Featured in Nature Reviews Cancer, Cancer Discovery, Nature Biotechnology, and Fred Hutch News.

Nonsense-mediated mRNA decay uses complementary mechanisms to suppress mRNA and protein accumulation
Udy DB, Bradley RK
Life Science Alliance doi:10.26508/lsa.202101217 (2021)

Coordinated mis-splicing of TMEM14C and ABCB7 causes ring sideroblast formation in SF3B1-mutant myelodysplastic syndrome
Clough CA, Pangallo J, Sarchi M, Ilagan JO, North K, Bergantinos R, Stolla MC, Naru J, Nugent P, Kim E, Stirewalt DL, Subramaniam AR, Abdel-Wahab O, Abkowitz JL, Bradley RK^†, Doulatov S^†
Blood doi:10.1182/blood.2021012652 (2021) ^†co-corresponding authors

Discovery of synthetic lethal and tumor suppressor paralog pairs in the human genome
Parrish PCR*, Thomas JD*, Gabel AM, Kamlapurkar S, Bradley RK, Berger AH
Cell Reports 36, 109597 (2021) *co-first authors

Integrative oncogene-dependency mapping identifies RIT1 vulnerabilities and synergies in lung cancer
Vichas A*, AK Riley*, Nkinsi NT, Kamlapurkar S, Parrish PCR, Lo A, Duke F, Chen J, Fung I, Watson J, Rees M, Gabel AM, Thomas JD, Bradley RK, Lee JK, Hatch EM, Baine MK, Rekhtman N, Ladanyi M, Piccioni F, Berger AH
Nature Communications 12:4789 (2021) *co-first authors

ZBTB33 is mutated in clonal hematopoiesis and myelodysplastic syndromes and impacts RNA splicing
Beauchamp EM, Leventhal M, Bernard E, Hoppe ER, Todisco G, Creignou M, Gallì A, Castellano CA, McConkey M, Tarun A, Wong W, Schenone M, Stanclift C, Tanenbaum B, Malolepsza E, Nilsson B, Bick AG, Weinstock JS, Miller M, Niroula A, Dunford A, Taylor-Weiner A, Wood T, Barbera A, Anand S; Psaty BM, Desai P, Cho MH, Johnson AD, Loos R; MacArthur DG, Lek M; Neuberg DS, Lage K, Carr SA, Hellstrom-Lindberg E, Malcovati L, Papaemmanuil E, Stewart C, Getz G, Bradley RK, Jaiswal S, Ebert BL
Blood Cancer Discovery 2:500-517 (2021)

Pharmacologic modulation of RNA splicing enhances anti-tumor immunity
Lu SX*, De Neef E*, Thomas JD*, Sabio E, Rousseau B, Gigoux M, Knorr DA, Greenbaum B, Elhanati Y, Hogg SJ, Chow A, Ghosh A, Xie A, Zamarin D, Cui D, Erickson C, Singer M, Cho H, Wang E, Lu B, Durham BH, Shah H, Chowell D, Gabel AM, Shen Y, Liu J, Jin J, Rhodes MC, Taylor RE, Molina H, Wolchok JD, Merghoub T, Diaz LA, Abdel-Wahab O^†, Bradley RK^†
Cell 184:4032-4047 (2021) *co-first authors; ^†co-corresponding authors

Featured in The New England Journal of Medicine, Nature, Cancer Discovery, Signal Transduction and Targeted Therapy, GeekWire, Fred Hutch News, and Memorial Sloan Kettering News.

Characterization of neoantigen-specific T cells in cancer resistant to immune checkpoint therapies
Li S, Simonia Y, Zhuanga S, Gabel A, Mag S, Cheeg J, Islasa L, Cessnaa A, Creaneyg J, Bradley RK, Redwood A, Robinson BW, Newell EW
PNAS 118:e2025570118 (2021)

Minor intron retention drives clonal hematopoietic disorders and diverse cancer predisposition
Inoue D*, Polaski JT*, Taylor J*, Castel P, Chen S, Kobayashi S, Hogg SJ, Hayashi Y, Pineda JMB, El Marabti E, Erickson C, Knorr K, Fukumoto M, Yamazaki H, Tanaka A, Fukui C, Lu SX, Durham BH, Liu B, Wang E, Mehta S, Zakheim D, Garippa R, Penson A, Chew G-L, McCormick F, Bradley RK^†, Abdel-Wahab O^†
Nature Genetics 53:707-718 (2021) *co-first authors; ^†co-corresponding authors

Featured in Cancer Discovery.

Convergent organization of aberrant MYB complex controls oncogenic gene expression in acute myeloid leukemia
Takao S, Forbes L, Uni M, Cheng S, Pineda JMB, Tarumoto Y, Cifani P, Minuesa G, Chen C, Kharas MG, Bradley RK, Vakoc C, Koche RP, Kentsis A
eLife 10:e65905 (2021)

Short H2A histone variants are expressed in cancer
Chew G-L, Bleakley M, Bradley RK, Malik HS, Henikoff S, Molaro A, Sarthy J
Nature Communications 12:490 (2021)

Featured in Nature Reviews Genetics.

The origins and consequences of UPF1 variants in pancreatic adenosquamous carcinoma
Polaski JT, Udy DB, Escobar-Hoyos LF, Askan G, Leach SD, Ventura A, Kannan R^†, Bradley RK^†
eLife 10:e62209 (2021) ^†co-corresponding authors

Single-cell genomics reveals the genetic and molecular bases for escape from mutational epistasis in myeloid neoplasms
Taylor J*, Mi X*, North KD*, Binder M*, Penson A, Lasho TL, Knorr K, Haddadin M, Liu B, Pangallo J, Benbarche S, Wiseman DH, Tefferi A, Halene S, Liang Y, Patnaik MM, Bradley RK, Abdel-Wahab O
Blood doi:10.1182/blood.2020006868 (2020) *equal contribution

Featured in Blood.

Altered RNA splicing by mutant p53 activates oncogenic RAS signaling in pancreatic cancer
Escobar-Hoyos LF, Penson A, Kannan R, Cho H, Pan C-H, Singh RK, Apken LH, Hobbs GA, Luo R, Lecomte N, Babu S, Pan FC, Alonso-Curbelo D, Morris JP, Askan G, Grbovic-Huezo O, Ogrodowski P, Bermeo J, Saglimbeni J, Cruz CD, Ho Y-J, Lawrence SA, Melchor JP, Goda GA, Bai K, Pastore A, Hogg SJ, Raghavan S, Bailey P, Chang DK, Biankin A, Shroyer KR, Wolpin BM, Aguirre AJ, Ventura A, Taylor B, Der CJ, Dominguez D, Kümmel D, Oeckinghaus A, Lowe SW, Bradley RK^†, Abdel-Wahab O^†, Leach SD^†
Cancer Cell 38:1–14 (2020) ^†co-senior authors

Transgenic mice expressing tunable levels of DUX4 develop characteristic facioscapulohumeral muscular dystrophy-like pathophysiology ranging in severity
Jones TI, Chew G-L, Barraza-Flores P, Schreier S, Ramirez M, Wuebbles RD, Burkin DJ, Bradley RK, Jones PL
Skeletal Muscle 10:8 (2020)

Recurrent SRSF2 mutations in MDS affect both splicing and NMD
Rahman MA, Lin K-T, Bradley RK, Abdel-Wahab O, Krainer AR
Genes & Development 34:1–15 (2020)

Rare and private spliceosomal gene mutations drive partial, complete, and dual phenocopies of hotspot alterations
Pangallo J, Kiladjian J-J, Cassinat B, Renneville A, Taylor J, Polaski JT, North K, Abdel-Wahab O, Bradley RK
Blood doi:10.1182/blood.2019002894 (2020)

Featured in Blood.

RNA isoform screens uncover the essentiality and tumor suppressor activity of ultraconserved poison exons
Thomas JD, Polaski JT*, Feng Q*, De Neef EJ, Hoppe ER, McSharry MV, Pangallo J, Gabel AM, Belleville AE, Watson J, Nkinsi NT, Berger AH, Bradley RK
Nature Genetics 52:84–94 (2020) *equal contribution

Featured in Yahoo! News, FierceBiotech, GeekWire, and Fred Hutch News.

Spliceosomal disruption of the non-canonical BAF complex in cancer
Inoue D*, Chew G-L*, Liu B, Michel BC, Pangallo J, D’Avino AR, Hitchman T, North K, Lee SC-W, Bitner L, Block A, Moore AR, Yoshimi A, Escobar-Hoyos L, Cho H, Penson A, Lu SX, Taylor J, Chen Y, Kadoch C, Abdel-Wahab O^†, Bradley RK^†
Nature 574:432–436 (2019) *co-first authors; ^†co-corresponding authors

Coordinated alterations in RNA splicing and epigenetic regulation drive leukaemogenesis
Yoshimi A, Lin K-T, Wiseman DH, Rahman MA, Pastore A, Wang B, Lee SC-W, Micol J-B, Zhang XJ, de Botton S, Penard-Lacronique V, Stein EM, Cho H, Miles RE, Inoue D, Albrecht TR, Somervaille TCP, Batta K, Amaral F, Simeoni F, Wilks DP, Cargo C, Intlekofer AM, Levine RL, Dvinge H, Bradley RK, Wagner EJ, Krainer AR, Abdel-Wahab O
Nature 574:273–277 (2019)

RNA components of the spliceosome regulate tissue- and cancer-specific alternative splicing
Dvinge H^†, Guenthoer J, Porter PL, Bradley RK^†
Genome Research 29:1591–1604 (2019) ^†co-corresponding authors

DUX4 suppresses MHC class I to promote cancer immune evasion and resistance to checkpoint blockade
Chew G-L*, Campbell A*, De Neef E, Sutliff NA, Shadle SC, Tapscott SJ^†, Bradley RK^†
Developmental Cell 50:658–671.e7 (2019) *co-first authors; ^†co-corresponding authors

Featured in Nature Reviews Cancer, FierceBiotech, GeekWire, and Fred Hutch News.

The splicing factor U2AF1 contributes to cancer progression through a noncanonical role in translation regulation
Palangat M, Anastasakis DG, Fei DL, Lindblad KE, Bradley RK, Hourigan CS, Hafner M, Larson DR
Genes & Development 33:1–16 (2019)

Quantitative proteomics reveals key roles for post-transcriptional gene regulation in the molecular pathology of FSHD
Jagannathan S^†, Ogata Y, Gafken PR, Tapscott SJ^†, Bradley RK^†
eLife 8:e41740 (2019) ^†co-corresponding authors

Exon junction complex shapes the transcriptome by repressing recursive splicing
Blazquez L, Emmett W, Faraway R, Pineda JMB, Bajew S, Gohr A, Haberman N, Sibley CR, Bradley RK, Irimia M, Ule J
Molecular Cell 72:496–509 (2018)

Impaired hematopoiesis and leukemia development in mice with a conditional knock-in allele of a mutant splicing factor gene U2af1
Fei DL, Zhen T, Durham B, Ferrarone J, Zhang T, Garrett L, Yoshimi A, Abdel-Wahab O, Bradley RK, Liu P, and Varmus H
PNAS doi:10.1073/pnas.1812669115 (2018)

Synthetic lethal and convergent biological effects of cancer-associated spliceosomal gene mutations
Lee SC*, North K*, Kim E*, Jang E, Obeng E, Lu SX, Liu B, Inoue D, Yoshimi A, Ki M, Yeo M, Zhang XJ, Kim MK, Cho H, Chung YR, Taylor J, Durham BH, Kim YJ, Pastore A, Monette S, Palacino J, Seiler M, Buonamici S, Smith PG, Ebert BL, Bradley RK^†, Abdel-Wahab O^†
Cancer Cell 34:225–241 (2018) *co-first authors; ^†co-corresponding authors

Featured in Cancer Discovery.

Dissecting the contributions of cooperating gene mutations to cancer phenotypes and drug responses with patient-derived iPSCs
Chang C-J, Kotini AG, Olszewska M, Georgomanoli M, Teruya-Feldstein J, Sperber H, Sanchez R, DeVita R, Martins TJ, Abdel-Wahab O, Bradley RK, Papapetrou EP
Stem Cell Reports 10:1610–1624 (2018)

Most human introns are recognized via multiple and tissue-specific branchpoints
Pineda JMB, Bradley RK
Genes & Development 32:577–591 (2018)

Congenital myotonic dystrophy—an RNA-mediated disease across a developmental continuum
Jagannathan S, Bradley RK
Genes & Development 31:1067–1068 (2017)

The RNA surveillance factor UPF1 represses myogenesis via its E3 ubiquitin ligase activity
Feng Q, Jagannathan S, Bradley RK
Molecular Cell 67:239–251 (2017)

Featured in Bioessays.

Wild-type U2AF1 antagonizes the splicing program characteristic of U2AF1-mutant tumors and is required for cell survival
Fei DL^†, Motowski H, Chatrikhi R, Prasad S, Yu J, Gao S, Kielkopf CL^†, Bradley RK^†, Varmus H^†
PLoS Genetics 12(10):e1006384 (2016) ^†co-corresponding authors

Systematic and functional characterization of novel androgen receptor variants arising from alternative splicing in the ligand-binding domain
Uo T, Dvinge H, Sprenger CC, Bradley RK, Nelson PS, Plymate SR
Oncogene 36:1440–1450 (2016)

Translational plasticity facilitates the accumulation of nonsense genetic variants in the human population
Jagannathan S, Bradley RK
Genome Research 26:1639–1650 (2016)

Model systems of DUX4 expression recapitulate the transcriptional profile of FSHD cells
Jagannathan S*, Shadle S*, Resnick R, Snider L, Tawil RN, van der Maarel SM, Bradley RK^†, Tapscott SJ^†
Human Molecular Genetics 25:4419–4431 (2016) *co-first authors; ^†co-senior authors

RNA splicing factors as oncoproteins and tumour suppressors
Dvinge H*, Kim E*, Abdel-Wahab O^†, Bradley RK^†
Nature Reviews Cancer 16:413–430 (2016) *co-first authors; ^†co-senior authors

Modulation of splicing catalysis for therapeutic targeting of leukemia with mutations in genes encoding spliceosomal proteins
Lee SC*, Dvinge H*, Kim E, Cho H, Micol JB, Chung YR, Durham BH, Yoshimi A, Kim YJ, Thomas M, Lobry C, Chen CW, Pastore A, Taylor J, Wang X, Krivtsov A, Armstrong SA, Palacino J, Buonamici S, Smith PG, Bradley RK^†, Abdel-Wahab O^†
Nature Medicine 22:672–678 (2016) *co-first authors; ^†co-senior authors

Featured in F1000 and Cancer Discovery.

Spliceosomal gene mutations in myelodysplasia: molecular links to clonal abnormalities of hematopoiesis
Inoue D, Bradley RK, Abdel-Wahab O
Genes & Development 30:989–1001 (2016)

The molecular taxonomy of primary prostate cancer
The Cancer Genome Atlas Research Network
Cell 163:1011–1025 (2015)

Expression of androgen receptor splice variants in clinical breast cancers
Hickey TE, Irvine CM, Dvinge H, Tarulli GA, Hanson AR, Ryan NK, Pickering MA, Birrell SN, Hu DG, Mackenzie PI, Russell R, Caldas C, Raj GV, Dehm SM, Plymate SR, Bradley RK, Tilley WD, Selth LA
Oncotarget 10.18632/oncotarget.6296 (2015)

Integrative clinical genomics of advanced prostate cancer
Robinson D, Van Allen EM, et al
Cell 161:1215–1228 (2015)

SRSF2 mutations contribute to myelodysplasia by mutant-specific effects on exon recognition
Kim E*, Ilagan JO*, Liang Y*, Daubner GM*, Lee SC-W, Ramakrishnan A, Li Y, Chung YR, Micol J-B, Murphy M, Cho H, Kim M-K, Zebari AS, Aumann S, Park CY, Buonamici S, Smith PG, Deeg HJ, Lobry C, Aifantis I, Modis Y, Allain FH-T, Halene S^†, Bradley RK^†, Abdel-Wahab O^†
Cancer Cell 27:617–630 (2015) *co-first authors; ^†co-senior authors

Featured in Nature Reviews Cancer, Cancer Cell, and Fred Hutch News.

Widespread intron retention diversifies most cancer transcriptomes
Dvinge H, Bradley RK
Genome Medicine 7:45 (2015)

A feedback loop between nonsense-mediated decay and the retrogene DUX4 in facioscapulohumeral muscular dystrophy
Feng Q, Snider L, Jagannathan S, Tawil R, van der Maarel SM, Tapscott SJ^†, Bradley RK^†
eLife 4:e04996 (2015) ^†co-senior authors

Featured in F1000.

Sample processing obscures cancer-specific alterations in leukemic transcriptomes
Dvinge H, Ries RE, Ilagan JO, Stirewalt DL, Meshinchi S, Bradley RK
PNAS 111:16802–16807 (2014)

Featured in F1000 and Fred Hutch News.

U2AF1 mutations alter splice site recognition in hematological malignancies
Ilagan JO*, Ramakrishnan A*, Hayes B, Murphy ME, Zebari AS, Bradley P, Bradley RK
Genome Research doi:10.1101/gr.181016.114 (2014) *co-first authors

Genome-wide RNAi screens in human brain tumor isolates reveal a novel viability requirement for PHF5A
Hubert CG*, Bradley RK*, Ding Y, Toledo CM, Herman J, Skutt-Kakaria K, Girard EJ, Davison J, Berndt J, Corrin P, Hardcastle J, Basom R, Delrow JJ, Webb T, Pollard SM, Lee J, Olson JM, Paddison PJ
Genes & Development 27(9):1032–1045 (2013) *co-first authors

Featured in Cancer Discovery.

Massive mitochondrial gene transfer in a parasitic flowering plant
Xi Z, Yuguo W, Bradley RK, Sugumaran M, Marx CJ, Rest JS, Davis CC
PLoS Genetics 9(2):e1003265 (2013)

Braveheart, a long non-coding RNA required for cardiovascular lineage commitment
Klattenhoff C, Scheuermann JC, Surface LE, Bradley RK, Fields PA, Steinhauser ML, Ding H, Butty VL, Torrey L, Haas S, Abo R, Tabebordbar M, Lee RT, Burge CB, Boyer LA
Cell 152(3):570–583 (2013)

Horizontal transfer of expressed genes in a parasitic flowering plant
Xi Z, Bradley RK, Wurdack KJ, Wong KM, Sugumaran M, Bomblies K, Rest JS, Davis CC
BMC Genomics 13:227 (2012)

Featured in The Economist and Scientific American.

The TAGteam motif facilitates binding of 21 sequence-specific transcription factors in the Drosophila embryo
Satija R, Bradley RK
Genome Research 22:656–665 (2012)

Alternative splicing of RNA triplets is often regulated and accelerates proteome evolution
Bradley RK, Merkin JM, Lambert N, Burge CB
PLoS Biology 10:e1001229 (2012)

Featured in Molecular Cell and Genome Biology.

Binding site turnover produces pervasive quantitative changes in transcription factor binding between closely related Drosophila species
Bradley RK*, Li XY*, Trapnell C, Davidson S, Pachter L, Chu HC, Tonkin LA, Biggin MD, Eisen MB
PLoS Biology 8:e1000343 (2010) *co-first authors

Featured in PLoS Biology.

Evolutionary triplet models of structured RNA
Bradley RK, Holmes I
PLoS Computational Biology 5(8):e1000483 (2009)

Evolutionary modeling and prediction of non-coding RNAs in Drosophila
Bradley RK, Uzilov AV, Skinner ME, Bendana YR, Barquist L, Holmes I
PLoS One 4(8):e6478 (2009)

Fast Statistical Alignment
Bradley RK, Roberts A, Smoot M, Juvekar S, Do J, Dewey C, Holmes I, Pachter L
PLoS Computational Biology 5:e1000392 (2009)

Tools for simulating evolution of aligned genomic regions with integrated parameter estimation
Varadarajan A, Bradley RK, Holmes I
Genome Biology 9:R147 (2008)

Specific alignment of structured RNA: stochastic grammars and sequence annealing
Bradley RK, Pachter L, Holmes I
Bioinformatics 24:2677–2683 (2008)

Evolution of genes and genomes on the Drosophila phylogeny
Drosophila 12 Genomes Consortium
Nature 450:203–218 (2007)

Transducers: an emerging probabilistic framework for modeling indels on trees
Bradley RK, Holmes I
Bioinformatics 23:3258–3262 (2007)

Xrate: a fast prototyping, training and annotation tool for phylo-grammars
Klosterman PS, Uzilov AV, Bendana YR, Bradley RK, Chao S, Kosiol C, Goldman N, Holmes I
BMC Bioinformatics 7:428 (2006)

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