A/Prof Ian Majewski, Lab Head | WEHI Researcher Profile

Q: How does DNA damage shape disease susceptibility over a lifetime?

The link between DNA damage and cancer is well established, but there is growing evidence of a contribute to other diseases. This project aims to accelerate the natural decay of the genome to determine how somatic mutations contribute to ageing and disease. We will manipulate DNA repair pathways in model systems to stimulate diverse forms of DNA damage and track their influence. We will go on to study how real-world stresses, like cancer therapy or chronic inflammation modify patterns of clonal selection.Project links/resources (optional): https://theconversation.com/time-doesnt-heal-all-wounds-how-dna-damage-as-we-age-causes-cancer-104107

Q: Cytidine deaminases – friend or foe?

Cytidine deaminases from the APOBEC-family make a major contribution to the mutational landscape of cancers from the bladder, breast and lung. These enzymes play a key role in viral defence, but often become misdirected and can trigger thousands of mutations in cellular DNA. We are investigating how APOBEC activity is regulated, how damage from these enzymes triggers cancer and how best to treat cancers with high levels of APOBEC.

Q: Defining the genotoxic impact of antiviral therapies

Many antiviral therapies target DNA or RNA synthesis to disrupt viral replication. It is exceedingly difficult to target such fundamental biological processes without causing collateral damage. This project will survey DNA damage from antiviral therapies, both in normal tissues and in cancers, to reveal genetic factors, transcriptional states and drug interactions that modify their impact.

About

The Majewski laboratory uses genomic approaches to identify germline and somatic alterations that drive cancer biology.

Ian completed a PhD in genetics at WEHI in 2008. He moved overseas to postdoc with René Bernards at the Netherlands Cancer Institute (NKI), where he studied genetic alterations in breast, colon and lung cancer, before returning to Melbourne to start his own laboratory.

Ian’s research has provided new insight into how DNA repair pathways modulate cancer risk. He is particularly interested in how different forms of DNA damage shape the earliest stages of cancer.

Education

Grants and funding

Publications

Selected publications from A/Prof Ian Majewski

Xu Z, Flensburg C, Bilardi RA, Majewski IJ. Uridine–cytidine kinase 2 potentiates the mutagenic influence of the antiviral β-d-N4-hydroxycytidine. Nucleic Acids Research. 2023;51(22):10.1093/nar/gkad1002

Chua CC, Anstee N, Flensburg C, Teh C, Ivey A, Amin N, Thijssen R, Bohlander SK, Kakadia PM, Xu Z, Fong CY, Ting S, Loo S, Tiong IS, Gray D, Fleming S, Davidson N, Roberts AW, Majewski I, Wei AH, Brown FC. Venetoclax Has Potent Efficacy in NPM1 mutated AML with Acquired Resistance Associated with Either Perturbed Pro-Survival Signalling or NPM1 wild-Type Populations. Blood. 2023;142(Supplement 1):10.1182/blood-2023-185321

Abdulla HD, Alserihi R, Flensburg C, Abeysekera W, Luo M-X, Gray DHD, Liu X, Smyth GK, Alexander WS, Majewski IJ, McCormack MP. Overexpression of Lmo2 initiates T-lymphoblastic leukemia via impaired thymocyte competition. Journal of Experimental Medicine. 2023;220(6):10.1084/jem.20212383

Thijssen R, Tian L, Anderson MA, Flensburg C, Jarratt A, Garnham AL, Jabbari JS, Peng H, Lew TE, Teh CE, Gouil Q, Georgiou A, Tan T, Djajawi TM, Tam CS, Seymour JF, Blombery P, Gray DHD, Majewski IJ, Ritchie ME, Roberts AW, Huang DCS. Single-cell multiomics reveal the scale of multi-layered adaptations enabling CLL relapse during venetoclax therapy. Blood. 2022;140(20):10.1182/blood.2022016040

Fang H, Yan HHN, Bilardi RA, Flensburg C, Yang H, Barbour JA, Siu HC, Turski M, Chew E, Xu Z, Lam ST, Sharma R, Xu M, Li J, Ip HW, Cheung CYM, Huen MSY, Sweet-Cordero EA, Majewski IJ, Leung SY, Wong JWH. Ganciclovir-induced mutations are present in a diverse spectrum of post-transplant malignancies. Genome Medicine. 2022;14(1):10.1186/s13073-022-01131-w

Schmidt B, Brown LM, Ryland GL, Lonsdale A, Kosasih HJ, Ludlow LE, Majewski IJ, Blombery P, Ekert PG, Davidson NM, Oshlack A. ALLSorts: a RNA-Seq subtype classifier for B-Cell Acute Lymphoblastic Leukemia.Blood Advances. 2022;6(14):10.1182/bloodadvances.2021005894

Thijssen R, Tian L, Flensburg C, Anderson MA, Jarratt A, Peng H, Majewski I, Tam C, Seymour J, Blombery P, Ritchie M, Huang D, Roberts A. S140: SINGLE‐CELL MULTIOMICS ANALYSES REVEAL COMPLEX INTRA‐PATIENT HETEROGENEITY IN RELAPSED CLL FOLLOWING VENETOCLAX THERAPY. HemaSphere. 2022;6:10.1097/01.hs9.0000843452.53281.c8

Palles C, West HD, Chew E, Galavotti S, Flensburg C, Grolleman JE, Jansen EAM, Curley H, Chegwidden L, Arbe-Barnes EH, Lander N, Truscott R, Pagan J, Bajel A, Sherwood K, Martin L, Thomas H, Georgiou D, Fostira F, Goldberg Y, Adams DJ, van der Biezen SAM, Christie M, Clendenning M, Thomas LE, Deltas C, Dimovski AJ, Dymerska D, Lubinski J, Mahmood K, van der Post RS, Sanders M, Weitz J, Taylor JC, Turnbull C, Vreede L, van Wezel T, Whalley C, Arnedo-Pac C, Caravagna G, Cross W, Chubb D, Frangou A, Gruber AJ, Kinnersley B, Noyvert B, Church D, Graham T, Houlston R, Lopez-Bigas N, Sottoriva A, Wedge D, Consortium GER, Consortium TC, Consortium W, Jenkins MA, Kuiper RP, Roberts AW, Cheadle JP, Ligtenberg MJL, Hoogerbrugge N, Koelzer VH, Rivas AD, Winship IM, Ponte CR, Buchanan DD, Power DG, Green A, Tomlinson IPM, Sampson JR, Majewski IJ, de Voer RM. Germline MBD4 deficiency causes a multi-tumor predisposition syndrome. American Journal of Human Genetics. 2022;109(5):10.1016/j.ajhg.2022.03.018

Flensburg C, Oshlack A, Majewski IJ. Detecting copy number alterations in RNA-Seq using SuperFreq. Bioinformatics. 2021;37(22):10.1093/bioinformatics/btab440

Tian L, Jabbari JS, Thijssen R, Gouil Q, Amarasinghe SL, Voogd O, Kariyawasam H, Du MRM, Schuster J, Wang C, Su S, Dong X, Law CW, Lucattini A, Prawer YDJ, Collar-Fernández C, Chung JD, Naim T, Chan A, Ly CH, Lynch GS, Ryall JG, Anttila CJA, Peng H, Anderson MA, Flensburg C, Majewski I, Roberts AW, Huang DCS, Clark MB, Ritchie ME. Comprehensive characterization of single-cell full-length isoforms in human and mouse with long-read sequencing. Genome Biology. 2021;22(1):10.1186/s13059-021-02525-6