Combined chemosensitivity and chromatin profiling prioritizes drug combinations in CLL
Open accessAbstract
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib has substantially improved therapeutic options for chronic lymphocytic leukemia (CLL). Although ibrutinib is not curative, it has a profound effect on CLL cells and may create new pharmacologically exploitable vulnerabilities. To identify such vulnerabilities, we developed a systematic approach that combines epigenome profiling (charting the gene-regulatory basis of cell state) with single-cell chemosensitivity profiling (quantifying cell-type-specific drug response) and bioinformatic data integration. By applying our method to a cohort of matched patient samples collected before and during ibrutinib therapy, we identified characteristic ibrutinib-induced changes that provide a starting point for the rational design of ibrutinib combination therapies. Specifically, we observed and validated preferential sensitivity to proteasome, PLK1, and mTOR inhibitors during ibrutinib treatment. More generally, our study establishes a broadly applicable method for investigating treatment-specific vulnerabilities by integrating the complementary perspectives of epigenetic cell states and phenotypic drug responses in primary patient samples.
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Several examples have documented the power of chemical screens in organoids or directly in patient material.
“To that end, several examples have documented the power of chemical screens in organoids175,176 or directly in patient material.177−179”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [178]
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Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2
Love, M. I., Huber, W., & Anders, S. (2014) · Genome Biology · doi:10.1186/s13059-014-0550-8 · Cited by 95,106 · see citing works
Fast gapped-read alignment with Bowtie 2
Langmead, B., & Salzberg, S. L. (2012) · Nature Methods · doi:10.1038/nmeth.1923 · Cited by 56,400 · see citing works
KEGG: Kyoto Encyclopedia of Genes and Genomes
Kanehisa, M. (2000) · Nucleic Acids Research · doi:10.1093/nar/28.1.27 · Cited by 37,077 · see citing works
KEGG: Kyoto Encyclopedia of Genes and Genomes
Ogata, H., Goto, S., Sato, K., Fujibuchi, W., Bono, H., & Kanehisa, M. (1999) · Nucleic Acids Research · doi:10.1093/nar/27.1.29 · Cited by 31,232 · see citing works
Model-based Analysis of ChIP-Seq (MACS)
Zhang, Y., Liu, T., Meyer, C. A., Eeckhoute, J., Johnson, D. S., Bernstein, B. E., Nusbaum, C., Myers, R. M., Brown, M., Li, W., et al. (2008) · Genome Biology · doi:10.1186/gb-2008-9-9-r137 · Cited by 18,386 · see citing works
Heinz, S., Benner, C., Spann, N., Bertolino, E., Lin, Y. C., Laslo, P., Cheng, J. X., Murre, C., Singh, H., & Glass, C. K. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.05.004 · Cited by 13,382 · see citing works
Buenrostro, J. D., Giresi, P. G., Zaba, L. C., Chang, H. Y., & Greenleaf, W. J. (2013) · Nature Methods · doi:10.1038/nmeth.2688 · Cited by 6,422 · see citing works
Sambamba: fast processing of NGS alignment formats
Tarasov, A., Vilella, A. J., Cuppen, E. P. J. G., Nijman, I. J., & Prins, P. (2015) · Bioinformatics · doi:10.1093/bioinformatics/btv098 · Cited by 2,339 · see citing works
Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia
Byrd, J. C., Furman, R. R., Coutre, S. E., Flinn, I. W., Burger, J. A., Blum, K. A., Grant, B., Sharman, J. P., Coleman, M., Wierda, W. G., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1215637 · Cited by 2,270 · see citing works
Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia
Burger, J. A., Tedeschi, A., Barr, P. M., Robak, T., Owen, C., Ghia, P., Bairey, O., Hillmen, P., Bartlett, N. L., Li, J., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1509388 · Cited by 1,587 · see citing works
Skewer: a fast and accurate adapter trimmer for next-generation sequencing paired-end reads
Jiang, H., Lei, R., Ding, S., & Zhu, S. (2014) · BMC Bioinformatics · doi:10.1186/1471-2105-15-182 · Cited by 1,525 · see citing works
Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib
Woyach, J. A., Furman, R. R., Liu, T.-M., Ozer, H. G., Zapatka, M., Ruppert, A. S., Xue, L., Li, D. H.-H., Steggerda, S. M., Versele, M., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1400029 · Cited by 1,275 · see citing works
Herman, S. E. M., Gordon, A. L., Hertlein, E., Ramanunni, A., Zhang, X., Jaglowski, S., Flynn, J., Jones, J., Blum, K. A., Buggy, J. J., et al. (2011) · Blood · doi:10.1182/blood-2011-01-328484 · Cited by 807 · see citing works
Ponader, S., Chen, S.-S., Buggy, J. J., Balakrishnan, K., Gandhi, V., Wierda, W. G., Keating, M. J., O'Brien, S., Chiorazzi, N., & Burger, J. A. (2012) · Blood · doi:10.1182/blood-2011-10-386417 · Cited by 640 · see citing works
Maddocks, K. J., Ruppert, A. S., Lozanski, G., Heerema, N. A., Zhao, W., Abruzzo, L., Lozanski, A., Davis, M., Gordon, A., Smith, L. L., et al. (2015) · JAMA Oncology · doi:10.1001/jamaoncol.2014.218 · Cited by 584 · see citing works
de Rooij, M. F. M., Kuil, A., Geest, C. R., Eldering, E., Chang, B. Y., Buggy, J. J., Pals, S. T., & Spaargaren, M. (2012) · Blood · doi:10.1182/blood-2011-11-390989 · Cited by 558 · see citing works
DGIdb: mining the druggable genome
Griffith, M., Griffith, O. L., Coffman, A. C., Weible, J. V., McMichael, J. F., Spies, N. C., Koval, J., Das, I., Callaway, M. B., Eldred, J. M., et al. (2013) · Nature Methods · doi:10.1038/nmeth.2689 · Cited by 527 · see citing works
Integrative annotation of chromatin elements from ENCODE data
Hoffman, M. M., Ernst, J., Wilder, S. P., Kundaje, A. B., Harris, R. S., Libbrecht, M., Giardine, B. M., Ellenbogen, P. M., Bilmes, J. A., Birney, E., et al. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks1284 · Cited by 521 · see citing works
LOLA: enrichment analysis for genomic region sets and regulatory elements in R and Bioconductor
Sheffield, N. C., & Bock, C. (2015) · Bioinformatics · doi:10.1093/bioinformatics/btv612 · Cited by 456 · see citing works
Self-citationThe B-cell receptor signaling pathway as a therapeutic target in CLL
Woyach, J. A., Johnson, A. J., & Byrd, J. C. (2012) · Blood · doi:10.1182/blood-2012-02-362624 · Cited by 412 · see citing works
B-cell receptor signaling in chronic lymphocytic leukemia
Stevenson, F. K., Krysov, S. V., Davies, A. J., Steele, A. J., & Packham, G. (2011) · Blood · doi:10.1182/blood-2011-06-338855 · Cited by 392 · see citing works
O'Brien, S. M., Furman, R. R., Coutre, S. E., Flinn, I. W., Burger, J. A., Blum, K. A., Sharman, J. P., Wierda, W. G., Jones, J. A., Zhao, W., et al. (2018) · Blood · doi:10.1182/blood-2017-10-810044 · Cited by 386 · see citing works
Griner, L. A. M., Guha, R., Shinn, P., Young, R. M., Keller, J. M., Liu, D., Goldlust, I. S., Yasgar, A., McKnight, C. G., Boxer, M. B., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1311846111 · Cited by 381 · see citing works
B cell receptor signaling in chronic lymphocytic leukemia
Burger, J. A., & Chiorazzi, N. (2013) · Trends in Immunology · doi:10.1016/j.it.2013.07.002 · Cited by 356 · see citing works
Large-scale imputation of epigenomic datasets for systematic annotation of diverse human tissues
Ernst, J., & Kellis, M. (2015) · Nature Biotechnology · doi:10.1038/nbt.3157 · Cited by 352 · see citing works
Burger, J. A., Landau, D. A., Taylor-Weiner, A., Bozic, I., Zhang, H., Sarosiek, K., Wang, L., Stewart, C., Fan, J., Hoellenriegel, J., et al. (2016) · Nature Communications · doi:10.1038/ncomms11589 · Cited by 345 · see citing works
O'Brien, S. M., Jones, J. A., Coutre, S. E., Mato, A. R., Hillmen, P., Tam, C. S. L., Österborg, A., Siddiqi, T., Thirman, M. J., Furman, R. R., et al. (2016) · The Lancet Oncology · doi:10.1016/s1470-2045(16)30212-1 · Cited by 339 · see citing works
Herman, S. E. M., Mustafa, R. Z., Gyamfi, J., Pittaluga, S., Chang, S., Chang, B. Y., Farooqui, M. Z. H., & Wiestner, A. U. (2014) · Blood · doi:10.1182/blood-2014-02-548610 · Cited by 246 · see citing works
Deng, J., Isik, E., Fernandes, S. M., Brown, J. R., Letai, A. G., & Davids, M. S. (2017) · Leukemia · doi:10.1038/leu.2017.32 · Cited by 198 · see citing works
Chen, S.-S., Chang, B. Y., Chang, S., Tong, T., Ham, S. D., Sherry, B. A., Burger, J. A., Rai, K. R., & Chiorazzi, N. (2015) · Leukemia · doi:10.1038/leu.2015.316 · Cited by 188 · see citing works
The evolutionary landscape of chronic lymphocytic leukemia treated with ibrutinib targeted therapy
Landau, D. A., Sun, C., Rosebrock, D., Herman, S. E. M., Fein, J., Sivina, M., Underbayev, C., Liu, D., Hoellenriegel, J., Ravichandran, S., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-02329-y · Cited by 176 · see citing works
Snijder, B., Vladimer, G. I., Krall, N., Miura, K., Schmolke, A.-S., Kornauth, C., de la Fuente, O. L., Choi, H.-S., van der Kouwe, E., Gültekin, S., et al. (2017) · The Lancet Haematology · doi:10.1016/s2352-3026(17)30208-9 · Cited by 175 · see citing works
Self-citationManaging drug resistance in cancer: lessons from HIV therapy
Bock, C., & Lengauer, T. (2012) · Nature reviews. Cancer · doi:10.1038/nrc3297 · Cited by 158 · see citing works
Self-citationDrug-perturbation-based stratification of blood cancer
Dietrich, S., Oleś, M., Lu, J., Sellner, L., Anders, S., Velten, B., Wu, B., Hüllein, J., Liberio, M. D. S., Walther, T., et al. (2017) · Journal of Clinical Investigation · doi:10.1172/jci93801 · Cited by 147 · see citing works
Rendeiro, A. F., Schmidl, C., Strefford, J. C., Walewska, R., Davis, Z., Farlik, M., Oscier, D., & Bock, C. (2016) · Nature Communications · doi:10.1038/ncomms11938 · Cited by 146 · see citing works
Self-citationDrug-perturbation-based stratification of blood cancer
Dietrich, S., Oleś, M., Lu, J., Sellner, L., Anders, S., Velten, B., Wu, B., Hüllein, J., Libério, M. S., Walther, T., et al. (2017) · Kölner Universitäts PublikationsServer (Universität zu Köln) · doi:10.17863/cam.20903 · Cited by 111 · see citing works
Shehata, M. M., Schnabl, S., Demirtas, D., Hilgarth, M., Hubmann, R., Ponath, E., Badrnya, S., Lehner, C., Hoelbl‐Kovacic, A., Duechler, M., et al. (2010) · Blood · doi:10.1182/blood-2009-10-248054 · Cited by 109 · see citing works
Self-citationBurger, J. A., Li, K. W., Keating, M. J., Sivina, M., Amer, A. M., Garg, N., Ferrajoli, A., Huang, X., Kantarjian, H. M., Wierda, W. G., et al. (2017) · JCI Insight · doi:10.1172/jci.insight.89904 · Cited by 95 · see citing works
Giulino-Roth, L. G., van Besien, H. J., Dalton, T. C., Totonchy, J. E., Rodina, A., Taldone, T., Bolaender, A., Erdjument‐Bromage, H., Sadek, J., Chadburn, A., et al. (2017) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-16-0848 · Cited by 95 · see citing works
Global survey of the immunomodulatory potential of common drugs
Vladimer, G. I., Snijder, B., Krall, N., Bigenzahn, J. W., Huber, K. V. M., Lardeau, C.-H., Sanjiv, K., Ringler, A., Berglund, U. W., Sabler, M., et al. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2360 · Cited by 87 · see citing works
Self-citationLipoprotein lipase expression is a novel prognostic factor in B-cell chronic lymphocytic leukemia
Nückel, H., Hüttmann, A., Klein‐Hitpaß, L., et al. (2006) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428190500464161 · Cited by 56 · see citing works
Ezell, S. A., Mayo, M., Bihani, T., Tepsuporn, S., Wang, S., Passino, M. A., Grosskurth, S. E., Collins, M., Parmentier, J. M., Reimer, C., et al. (2014) · Oncotarget · doi:10.18632/oncotarget.2071 · Cited by 54 · see citing works
Murray, M. Y., Zaitseva, L., Auger, M. J., Craig, J. I. O., MacEwan, D. J., Rushworth, S. A., & Bowles, K. M. (2015) · Cell Cycle · doi:10.1080/15384101.2014.998067 · Cited by 53 · see citing works
Tao, Y., Li, Z.-H., Du, W., et al. (2017) · Oncology Reports · doi:10.3892/or.2017.5417 · Cited by 38 · see citing works
Bruton tyrosine kinase inhibition in chronic lymphocytic leukemia
Maddocks, K. J., & Jones, J. A. (2016) · Seminars in Oncology · doi:10.1053/j.seminoncol.2016.02.008 · Cited by 32 · see citing works
Targeting BTK through microRNA in chronic lymphocytic leukemia
Bottoni, A., Rizzotto, L., Lai, T.-H., Liu, C., Smith, L. L., Mantel, R., Reiff, S. D., El‐Gamal, D., Larkin, K. T. M., Johnson, A. J., et al. (2016) · Blood · doi:10.1182/blood-2016-07-727750 · Cited by 31 · see citing works
PLK1 is a binding partner and a negative regulator of FOXO3 tumor suppressor
Bucur, O., Stancu, A. L., Muraru, M. S., et al. (2014) · Discoveries · doi:10.15190/d.2014.8 · Cited by 25 · see citing works
Chari, A., Larson, S. M., Holkova, B., et al. (2018) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428194.2018.1443337 · Cited by 24 · see citing works
Proteasome inhibitor carfilzomib complements ibrutinib’s action in chronic lymphocytic leukemia
Lamothe, B., Cervantes-Gomez, F., Sivina, M., Wierda, W. G., Keating, M. J., & Gandhi, V. V. (2015) · Blood · doi:10.1182/blood-2014-07-585364 · Cited by 23 · see citing works
IBRUTinib: BRUTe force against bortezomib-resistant myeloma cells
Xian, L., Huff, C. A., & Resar, L. M. S. (2015) · Cell Cycle · doi:10.1080/15384101.2015.1022058 · Cited by 1 · see citing works
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Grandi, F. C., Modi, H., Kampman, L., & Corces, M. R. (2022) · Nature Protocols · doi:10.1038/s41596-022-00692-9 · Cited by 557 · see citing works
Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence
Duran-Frigola, M., Cigler, M., & Winter, G. E. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.2c11098 · Cited by 50 · see citing works
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Heinemann, T., Kornauth, C., Severin, Y., Vladimer, G. I., Pemovska, T., Hadzijusufovic, E., Agis, H., Krauth, M.-T., Sperr, W. R., Valent, P., et al. (2022) · Blood Cancer Discovery · doi:10.1158/2643-3230.bcd-21-0219 · Cited by 28 · see citing works
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- Authors
- Schmidl, C., Vladimer, G. I., Rendeiro, A. F., Schnabl, S., Krausgruber, T., Taubert, C., Krall, N., Pemovska, T., Araghi, M., Snijder, B., Hubmann, R., Ringler, A., Runggatscher, K., Demirtas, D., de la Fuente, O. L., Hilgarth, M., Skrabs, C., Porpaczy, E., Gruber, M., Hoermann, G., Kubicek, S., Staber, P. B., Shehata, M., Superti-Furga, G., Jäger, U., & Bock, C.
- Affiliations
- Austrian Academy of Sciences (AT)
- Comprehensive Cancer Center Vienna (AT)
- Medical University of Vienna (AT)
- Corresponding author
- Bock, Christoph
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2019-01-28
- Volume
- 15
- Issue
- 3
- Pages
- 232-240
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC6746620
- OpenAlex
- W2914351181
- Cited by
- 39
- References
- 50
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 5 · 2022: 10 · 2021: 8 · 2020: 11 · 2019: 1
- FWCI
- 4.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (147897)
- Nature
- Cilag
- Topics
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
- Keywords
- chronic lymphocytic leukemia, ibrutinib, BTK inhibitors, drug combination design, epigenetic profiling, chromatin profiling, proteasome inhibitors, PLK1 inhibitors, mTOR inhibitors, drug response
- MeSH terms
- Agammaglobulinaemia Tyrosine Kinase, Polo-Like Kinase 1, Adenine, Chromatin, Drug Combinations, Humans, Piperidines, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Pyrazoles, Pyrimidines, Signal Transduction, Leukemia, Lymphocytic, Chronic, B-Cell, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Drug Resistance, Neoplasm, Epigenesis, Genetic, Protein Kinase Inhibitors, Epigenomics, TOR Serine-Threonine Kinases, Single-Cell Analysis
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