Genome-wide pan-haematopoietic transposon screening for oncogenic network discovery in mice

• Applicant: Professor Dr. Roland Rad
• Subject Area: Hematology, Oncology ; General Genetics and Functional Genome Biology
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 386625870

• Final Report Year: 2022

Final Report Abstract

Whilst genome sequencing proved very powerful for the identification of genetic alterations in cancer, understanding other levels of gene dysregulation remains a challenge. There is, for example, a lack of tools to systematically search for targets or effector pathways downstream of mutated human cancer genes, or to pinpoint cancer drivers that are not mutated but are among the thousands of epigenetically, transcriptionally or post- transcriptionally dysregulated genes in a cancer cell. To address these issues, we developed new genomic tools allowing systematic interrogation of the non-mutated cancer genome and regulome. By using these systems for genome-wide screening in mice we discovered large numbers of genes and gene regulatory elements driving different haematopoietic cancers. Downstream mechanistic studies on selected discoveries gave new insights into the biology and evolution of different hematopoietic malignancies and their subentities. We also developed new mouse models, CRISPR genomic technologies and computational methods for structural and functional cancer genomics in mice. These resources are broadly applicable and already being widely used around the globe in different research areas.

Publications

• Genome-wide transposon screening and quantitative insertion site sequencing (QiSeq) for cancer gene discovery in mice. Nature Protocols 2017, Feb;12(2):289-309
  Friedrich M, Rad L, Bronner I, Strong A, Wang W, Weber J, Mayho M, Ponstingl H, Engleitner T, Grove C, Pfaus A, Saur D, Cadinanos J, Quail MA, Vassiliou GS, Liu P, Bradley A, Rad R
  (See online at https://doi.org/10.1038/nprot.2016.164)
• Engineering CRISPR mouse models of cancer. Curr Opin Genet Dev. 2019 Feb;54:88-96
  Weber J, Rad R
  (See online at https://doi.org/10.1016/j.gde.2019.04.001)
• Functionalizing cancer genomes in the era of big data. Curr Opin Genet Dev. 2019 Feb;54:iii-vi
  Rad R, Boutros M
  (See online at https://doi.org/10.1016/j.gde.2019.06.011)
• PiggyBac transposon tools for recessive screening identify B-cell lymphoma drivers in mice. Nature Commun. 2019 Mar 29;10(1):1415
  Weber J, de la Rosa J, Grove CS, Schick M, Rad L, Baranov O, Strong A, Pfaus A, Friedrich MJ, Engleitner T, Lersch R, Öllinger R, Grau M, Menendez IG, Martella M, Kohlhofer U, Banerjee R, Turchaninova MA, Scherger A, Hoffman GJ, Hess J, Kuhn LB, Ammon T, Kim J, Schneider G, Unger K, Zimber-Strobl U, Heikenwälder M, Schmidt-Supprian M, Yang F, Saur D, Liu P, Steiger K, Chudakov DM, Lenz G, Quintanilla-Martinez L, Keller U, Vassiliou GS, Cadiñanos J, Bradley A, Rad R
  (See online at https://doi.org/10.1038/s41467-019-09180-3)
• PiggyBac Transposon-Based Insertional Mutagenesis in Mice. Methods Mol Biol. 2019;1907:171
  Friedrich MJ, Bronner IF, Liu P, Bradley A, Rad R
  (See online at https://doi.org/10.1007/978-1-4939-8967-6_14)
• Analysis pipelines for cancer genome sequencing in mice. Nature Protocols. 2020 Feb;15(2):266-315
  Lange S, Engleitner T, Mueller S, Maresch R, Zwiebel M, González-Silva L, Schneider G, Banerjee R, Yang F, Vassiliou GS, Friedrich MJ, Saur D, Varela I, Rad R
  (See online at https://doi.org/10.1038/s41596-019-0234-7)
• In vivo functional screening for systems-level integrative cancer genomics. Nat Rev Cancer. 2020 Oct;20(10):573-593
  Weber J, Braun CJ, Saur D, Rad R
  (See online at https://doi.org/10.1038/s41568-020-0275-9)
• Linkage of genetic drivers and strain-specific germline variants confound mouse cancer genome analyses. Nature Commun. 2020 Sep 8;11(1):4474
  Mueller S, Lange S, Collins KAN, Krebs S, Blum H, Schneider G, Rad L, Saur D, Rad R
  (See online at https://doi.org/10.1038/s41467-020-18095-3)
• Genetic alterations of the SUMO isopeptidase SENP6 drive lymphomagenesis and genetic instability in diffuse large B-cell lymphoma. Nature Commun 2022 Jan 12;13(1):281
  Schick M, Zhang L, Maurer S, Maurer HC, Isaakaidis K, Schneider L, Patra U, Schunck K, Rohleder E, Hofstetter J, Baluapuri A, Scherger AK, Slotta-Huspenina J, Hettler F, Weber J, Engleitner T, Maresch R, Slawska J, Lewis R, Istvanffy R, Habringer S, Steiger K, Baiker A, Oostendorp RAJ, Miething C, Lenhof HP, Bassermann F, Chapuy B, Wirth M, Wolf E, Rad R, Müller S, Keller U
  (See online at https://doi.org/10.1038/s41467-021-27704-8)