Vyas Group: Mechanisms of genomic and epigenomic instability in TP53 mutant AML

Paresh Vyas, Ross Chapman, KJ Patel

Genetic changes (point mutations or copy number abnormalities) that disrupt function of TP53 occur in ~ 10% of patients with Acute Myeloid Leukaemia (AML), the most aggressive adult leukaemia. TP53 mutant (TP53m) AML has a prognosis of only ~ 6 months. TP53m is often associated with complex chromosomal changes arising from chromothripis. The mechanisms that trigger chromothripis and lead to the selection of specific chromosomal rearrangements in TP53m AML is unclear. Understanding these mechanisms may lead to novel therapeutic approaches for this AML subtype for which there is high unmet need.

About the Research

We have spent the last decade characterising in great detail, normal human haeemopietic stem/progenitor biology (Karamitros et al Nature Immunology 2018 and Aksoz et al Science Immunology 2024). Blood stem progenitor cells acquire genetic and epigenetic changes gradually transform them into leukaemia propagating stem cell (Goardon et al Cancer Cell 2011; Quek et al Journal of Experimental Medicine 2016; Labuhn et al Cancer Cell 2019; Genua et al Cancer Cell 2020; Turkajl et al Cell Stem Cell 2023; Jakobsen et al Cell Stem Cell 2024). More recently, we have developed quantitative models to detect selection and infer the clonal stem/progenitor dynamics (age of clones, clonal division rates, stem cell numbers) (Korber et al 2024). Over the last 3 years we have been characterising a cohort of 45 TP53m AML (bulk whole genome sequencing, single cell multi-omic RNA, ATAC-Seq and immunophenotyping profiling). In these AML samples there are a hierarchy of recurrent driver mutations and complex chromosomal changes that arise by chromothripis and that are selected to provide clonal advantage. We wish to understand the mechanisms by chromothripis occurs and the mechanisms underlying the selection of genetic (copy number changes) and corresponding chromatin changes.

Training Opportunities

Training will be provided in studying genome instability leading to chromothripism, HSC and progenitor biology thata re the cellular template for selection. From a methods point of view the applicant will conduct and be given experience and training in the wet lab molecular and cellular techniques and advanced computational analysis including advanced flow cytometry including FACS sorting, in vitro and in vivo CRISPR/Cas9-based genome editing screens and library screening technologies, advanced mouse genetics and bioinformatics. Candidates will also have exposure to mathematical modelling and machine learning.

Students will be enrolled on the MRC Weatherall Institute of Molecular Medicine DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence, and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

As well as the specific training detailed above, students will have access to a wide range of seminars and training opportunities through the many research institutes and centres based in Oxford.

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

Additional Supervisors

1	Professor KJ Patel
2	Professor Ross Chapman

Publications

1	Karamitros D, Stoilova B, Aboukhalil Z, Hamey F, Reinisch A, Samitsch M, Quek L, Otoo G, Repapi E, Doondeea J, Usukhbayar B, Calvo J, Taylor S, Goardon N, Six E, Pflumio F, Porcher C, Majeti R, Gottgens B, Vyas P. Functional and transcriptional heterogeneity of human hemopoietic lympho-myeloid progenitors at the single cell level. Nature Immunology, Jan;19(1):85-97. Doi: 10.1038/s41590-017-0001-2. (2018). PMID: 29167569.
2	Aksöz M, Gafencu G-A, Stoilova B, Buono M, Zhang Y, Turkalj S, Meng Y, Jakobsen NA, Metzner M, Clark S-A, Beveridge R, Thongjuea S, Vyas P^* and Nerlov C^. Evolutionarily conserved hematopoietic stem cell heterogeneity and age-associated stem cell platelet bias. Science Immunology, In Press. Joint last authors.
3	Goardon N, Marchi E, Atzberger A, Quek L, Schuh A, Woll P, Mead A, Alford KA, Rout R, Chaudhury S, Gilkes A, Knapper S, Soneji S, Beldjord K, Begum S, Rose S, Geddes N, Griffiths M, Standen G, Sternberg A, Cavenagh J, Hunter H, BowenD, Killick S, Robinson L, Price A, Macintyre E, Virgo P, Burnett A, Craddock C, Enver T, Jacobsen SEW, Porcher C and Vyas P. Co-existence of LMPP-like and GMP-like Leukemia Stem Cells in Acute Myeloid Leukemia. Cancer Cell, Jan 18;19(1):138-52. Doi: 10.1016/j.ccr.2010.12.012. (2011). PMID: 21251617.
4	Quek L, David M, Kennedy A, Metzner M_, Amatangelo M, Shih A, Stoilova B, Quivoron C, Heiblig M, Willekens C, Saada V, Peniket A, Bernard O, Agresta S, Yen K, MacBeth K, Stein E, Levine R_,De Botton S, Thakurta A, Penard-Lacronique V and Vyas P. Clonal Heterogeneity in Differentiation Response and Resistance to the IDH2 inhibitor Enasidenib in Acute Myeloid Leukemia. Nature Medicine, Aug 24(8):1167-1177. Doi: 10.1038/s41591-018-0115-6. (2018). PMID: 30013198.
5	Labuhn M, Perkins K, Papaemmanuil E, Matzk S, Varghese L, Amstislavskiy V, Risch T, Garnett C, Hernandez, D, Metzner M, Kenndy, A, Iotchkova V, Stoilova, B, Scheer C, Yoshida K, Schwarzer A, Taub J, Crispino JD., Weiss MJ, Hayashi A, Taga T, Ito E, Ogawa S, Reinhardt D, Yaspo ML, Campbell PJ, Roberts I, Constantinescu S, Vyas P, Heckl^,D, Klusmann JH. (Joint last authors). Mechanisms Of Progression Of Myeloid Preleukemia To Transformed Myeloid Leukemia In Children With Down Syndrome. Cancer Cell, Aug 12;36(2):123-138.310. Doi: 10.1016/j.ccell.2019.06.007 (2019). Joint last authors.
6	Genua C, Valletta S, Buono M, Stoilova B, Sweeney C, Rodriguez-Meira A, Grove A, Drissen R, Meng Y, Beveridge R, Aboukhalil Z, Karamitros D, Belderbos M, Bystrykh L, Thongjuea S, Vyas P, Nerlov C. C/EBPα and GATA-2 mutations induce bi-lineage acute erythroid leukemia through transformation of a neomorphic neutrophil-erythroid progenitor. Cancer Cell, Apr 14:S1535-6108(20)30162-8. doi: 10.1016/j.ccell.2020.03.022. Online ahead of print (2020). PMID: 32330454. *Joint last authors
7	Turkalj S, Jakobsen NA, Groom A, Metzner M, Riva SG, Gür ER, Usukhbayar B, Salazar MA, Hentges LD, Mickute G, Clark K, Sopp P, Davies JOJ, Hughes JR, Vyas P. GTAC enables parallel genotyping of multiple genomic loci with chromatin accessibility profiling in single cells. Cell Stem Cell, 2023 May 4;30(5):722-740.e11. doi: 10.1016/j.stem.2023.04.012. PMID: 37146586.
8	Jakobsen NA, Turkalj S, Zeng A, Stoilova B, Metzner M, Nagree MS, Shah S, Moore R, Usukhbayar B, Salazar MA, Gafencu GA, Kennedy A, Newman S, Kendrick BJL, Taylor AH, Afinowi-Luitz R, Gundle R, Watkins B, Wheway K, Beazley D, Murison A, Aguilar-Navarro AG, Flores-Figueroa E, Dakin SG, Carr AJ, Nerlov C, Dick JE, Xie SZ and Vyas P. Mutant Stem Cells In Clonal Hematopoeisis Are Selected By Overcoming Deletrious Effects of Inflammationa And Aging. Cell Stem Cell* (2024), Jun 19:S1934-5909(24)00207-8. doi: 10.1016/j.stem.2024.05.010. (2024). PMID: 38917807. *Joint last authors
9	Korber V, Jakobsen NA, Ansari-Pour N, Moore R, Claudino N, Metzner M, Thielecke E, Horsch F, Usukhbayar B, Angulo Salazar M, Newman S, Kendrick BJL, Taylor AH, Afinowi-Luitz R, Gundle R, Watkings B, Wheway K, Beaszley D, Dakin SG, Carr AJ, Vyas P, Hofer T. Detecting and quantifying clonal selection in somatic stem cells. Nature Genetics. (2024), Invited resubmission under review. *Joint last authors.

How to apply

All applications must be made using the University's online application form.

Find out more

1	Karamitros D, Stoilova B, Aboukhalil Z, Hamey F, Reinisch A, Samitsch M, Quek L, Otoo G, Repapi E, Doondeea J, Usukhbayar B, Calvo J, Taylor S, Goardon N, Six E, Pflumio F, Porcher C, Majeti R, Gottgens B, Vyas P. Functional and transcriptional heterogeneity of human hemopoietic lympho-myeloid progenitors at the single cell level. Nature Immunology, Jan;19(1):85-97. Doi: 10.1038/s41590-017-0001-2. (2018). PMID: 29167569.
2	Aksöz M, Gafencu G-A, Stoilova B, Buono M, Zhang Y, Turkalj S, Meng Y, Jakobsen NA, Metzner M, Clark S-A, Beveridge R, Thongjuea S, Vyas P^* and Nerlov C^. Evolutionarily conserved hematopoietic stem cell heterogeneity and age-associated stem cell platelet bias. Science Immunology, In Press. Joint last authors.
3	Goardon N, Marchi E, Atzberger A, Quek L, Schuh A, Woll P, Mead A, Alford KA, Rout R, Chaudhury S, Gilkes A, Knapper S, Soneji S, Beldjord K, Begum S, Rose S, Geddes N, Griffiths M, Standen G, Sternberg A, Cavenagh J, Hunter H, BowenD, Killick S, Robinson L, Price A, Macintyre E, Virgo P, Burnett A, Craddock C, Enver T, Jacobsen SEW, Porcher C and Vyas P. Co-existence of LMPP-like and GMP-like Leukemia Stem Cells in Acute Myeloid Leukemia. Cancer Cell, Jan 18;19(1):138-52. Doi: 10.1016/j.ccr.2010.12.012. (2011). PMID: 21251617.
4	Quek L, David M, Kennedy A, Metzner M_, Amatangelo M, Shih A, Stoilova B, Quivoron C, Heiblig M, Willekens C, Saada V, Peniket A, Bernard O, Agresta S, Yen K, MacBeth K, Stein E, Levine R_,De Botton S, Thakurta A, Penard-Lacronique V and Vyas P. Clonal Heterogeneity in Differentiation Response and Resistance to the IDH2 inhibitor Enasidenib in Acute Myeloid Leukemia. Nature Medicine, Aug 24(8):1167-1177. Doi: 10.1038/s41591-018-0115-6. (2018). PMID: 30013198.
5	Labuhn M, Perkins K, Papaemmanuil E, Matzk S, Varghese L, Amstislavskiy V, Risch T, Garnett C, Hernandez, D, Metzner M, Kenndy, A, Iotchkova V, Stoilova, B, Scheer C, Yoshida K, Schwarzer A, Taub J, Crispino JD., Weiss MJ, Hayashi A, Taga T, Ito E, Ogawa S, Reinhardt D, Yaspo ML, Campbell PJ, Roberts I, Constantinescu S, Vyas P, Heckl^,D, Klusmann JH. (Joint last authors). Mechanisms Of Progression Of Myeloid Preleukemia To Transformed Myeloid Leukemia In Children With Down Syndrome. Cancer Cell, Aug 12;36(2):123-138.310. Doi: 10.1016/j.ccell.2019.06.007 (2019). Joint last authors.
6	Genua C, Valletta S, Buono M, Stoilova B, Sweeney C, Rodriguez-Meira A, Grove A, Drissen R, Meng Y, Beveridge R, Aboukhalil Z, Karamitros D, Belderbos M, Bystrykh L, Thongjuea S, Vyas P, Nerlov C. C/EBPα and GATA-2 mutations induce bi-lineage acute erythroid leukemia through transformation of a neomorphic neutrophil-erythroid progenitor. Cancer Cell, Apr 14:S1535-6108(20)30162-8. doi: 10.1016/j.ccell.2020.03.022. Online ahead of print (2020). PMID: 32330454. *Joint last authors
7	Turkalj S, Jakobsen NA, Groom A, Metzner M, Riva SG, Gür ER, Usukhbayar B, Salazar MA, Hentges LD, Mickute G, Clark K, Sopp P, Davies JOJ, Hughes JR, Vyas P. GTAC enables parallel genotyping of multiple genomic loci with chromatin accessibility profiling in single cells. Cell Stem Cell, 2023 May 4;30(5):722-740.e11. doi: 10.1016/j.stem.2023.04.012. PMID: 37146586.
8	Jakobsen NA, Turkalj S, Zeng A, Stoilova B, Metzner M, Nagree MS, Shah S, Moore R, Usukhbayar B, Salazar MA, Gafencu GA, Kennedy A, Newman S, Kendrick BJL, Taylor AH, Afinowi-Luitz R, Gundle R, Watkins B, Wheway K, Beazley D, Murison A, Aguilar-Navarro AG, Flores-Figueroa E, Dakin SG, Carr AJ, Nerlov C, Dick JE, Xie SZ and Vyas P. Mutant Stem Cells In Clonal Hematopoeisis Are Selected By Overcoming Deletrious Effects of Inflammationa And Aging. Cell Stem Cell* (2024), Jun 19:S1934-5909(24)00207-8. doi: 10.1016/j.stem.2024.05.010. (2024). PMID: 38917807. *Joint last authors
9	Korber V, Jakobsen NA, Ansari-Pour N, Moore R, Claudino N, Metzner M, Thielecke E, Horsch F, Usukhbayar B, Angulo Salazar M, Newman S, Kendrick BJL, Taylor AH, Afinowi-Luitz R, Gundle R, Watkings B, Wheway K, Beaszley D, Dakin SG, Carr AJ, Vyas P, Hofer T. Detecting and quantifying clonal selection in somatic stem cells. Nature Genetics. (2024), Invited resubmission under review. *Joint last authors.