Mead Group: Gene-Environment Initiated Disease Progression in Myeloproliferative Neoplasms

Adam Mead

About the Research

The overarching aim of my research group is to improve the diagnosis, risk-stratification and treatment of myeloproliferative neoplasms (MPN), fuelled by a better understanding of the pathobiology of this largely incurable form of blood cancer. Using a combination of single-cell genomics, stem cell assays and in vivo models we have uncovered a key role for inflammatory signalling and identified new ways to target leukaemia stem cells. Inflammation causes a suppression of normal haematopoietic stem cells whilst in parallel promoting the fitness advantage, aberrant differentiation, therapy resistance and genetic evolution of mutant stem cells in chronic myeloid leukaemia (Nature Medicine 2017), MPN (Molecular Cell 2019 & 2020) and FLT3 mutant myeloid neoplasms (J Exp Med 2017). A crucial conceptual advance made in our recent work was to describe how inflammation promotes genetic evolution of p53 mutant stem cells in blast phase MPN (Nature Genetics, 2023), with broad implications for the role of p53 mutations in cancer. We were the first to characterise leukaemia stem cells and thereby uncover novel therapeutic targets in juvenile myelomonocytic leukaemia (Journal of Experimental Medicine, 2021) and early thymic progenitor leukaemia (Cancer Cell, 2018). We used genetic lineage tracing in monozygotic twins to demonstrate the prolonged evolutionary dynamics of MPN, which can arise in utero despite presenting clinically decades later in adults (Nature Medicine, 2022). Most recently, we conducted genetic analysis of samples collected in the MAJIC study which majorly advanced the field by demonstrating that JAK2 inhibitor treatment improves event free survival and eradicates mutant stem cells in polycythaemia vera (Journal of Clinical Oncology, 2023).

Students interested in joining the laboratory will have the opportunity to apply the above approaches to study how inflammation and triggers for inflammation promotes DNA damage and clonal evolution in TP53 mutant blast phase MPN a blood cancer associated with a very poor prognosis. Projects employ a range of cutting-edge techniques including in vivo mouse models, single-cell multiomic analyses, spatial transcriptomics, stem cell assays and computational biology methods.

Training Opportunities

The Mead laboratory leads on single-cell research at the WIMM and the student will gain a state of the art training in this exciting field. Prof Mead maintains close links with the clinical NHS haematology department in Oxford, key to obtain patient samples and enable the translation of scientific research into clinical practice. Previous students in the Mead Laboratory have conducted highly successful DPhils. For example, Christopher Booth (completed Jan 2018) was awarded the Ita Askonas Medal for best DPhil student presentation at the WIMM day in 2016, the RDM Graduate Prize in 2018 and published a first author paper in Cancer Cell, 2018. Alba Rodriguez-Meira (year 4 DPhil student in the Mead Lab) developed TARGET-seq, was awarded the Ita Askonas Medal for best DPhil student presentation in 2018 and has first author papers in Molecular Cell (2019) and nature Genetics (2023). Professor Mead was awarded the RDM prize for excellent supervision in 2021.

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 Beth Psaila

Publications

1	Rodriguez-Meira A, Norfo, Wen S, Chédeville AL, Rahman H, O’Sullivan J, Wang G, Louka E, Kretzschmar WW, Paterson A, Brierley C, Martin J, Demeule C, Bashton M, Sousos N, Moralli D, Subha Meem L, Carrelha J, Wu B, Hamblin A, Guermouche H, Pasquier F, Marzac C, Girodon F, Vainchenker W, Drummond M, Harrison C, Chapman JR, Plo I, Jacobsen SE, Psaila B, Thongjuea S, Antony-Debré I^§, Mead AJ^§ Single-Cell Multi-Omics Identifies Chronic Inflammation as a Driver of TP53 mutant Leukaemic Evolution. Nature Genetics. 2023; in press. *equal contribution. ^§Joint corresponding authors.
2	Harrison CN, Nangalia J, Boucher R, Jackson A, Yap C, O'Sullivan J, Fox S, Ailts I, Dueck AC, Geyer HL, Mesa RA, Dunn WG, Nadezhdin E, Curto-Garcia N, Green A, Wilkins B, Coppell J, Laurie J, Garg M, Ewing J, Knapper S, Crowe J, Chen F, Koutsavlis I, Godfrey A, Arami S, Drummond M, Byrne J, Clark F, Mead-Harvey C, Baxter EJ, McMullin MF, Mead AJ. Ruxolitinib Versus Best Available Therapy for Polycythemia Vera Intolerant or Resistant to Hydroxycarbamide in a Randomized Trial. Journal of Clinical Oncology. 2023;41(19):3534-44.
3	Sousos N⁺, Ni Leathlobhair M⁺, Simoglou Karali C, Louka E, Bienz N, Royston D, Clark SA, Hamblin A, Howard K, Mathews V, George B, Roy A, Psaila B, Wedge DC, Mead AJ. In utero origin of myelofibrosis presenting in adult monozygotic twins. Nature Medicine. 2022. * Equal contribution and joint corresponding authors.
4	Louka E, Povinelli B, Rodriguez-Meira A, Buck G, Wen WX, Wang G, Sousos N, Ashley N, Hamblin A, Booth CAG, Roy A, Elliott N, Iskander D, de la Fuente J, Fordham N, O'Byrne S, Inglott S, Norfo R, Salio M, Thongjuea S, Rao A, Roberts I⁺, Mead AJ⁺. Heterogeneous disease-propagating stem cells in juvenile myelomonocytic leukemia. Journal of Experimental Medicine. 2021;218(2). ^+,* Equal contribution.
5	Psaila B, Wang G, Rodriguez-Meira A, Li R, Heuston EF, Murphy L, Yee D, Hitchcock IS, Sousos N, O'Sullivan J, Anderson S, Senis YA, Weinberg OK, Calicchio ML, Center NIHIS, Iskander D, Royston D, Milojkovic D, Roberts I, Bodine DM, Thongjuea S, Mead AJ. Single-Cell Analyses Reveal Megakaryocyte-Biased Hematopoiesis in Myelofibrosis and Identify Mutant Clone-Specific Targets. Molecular Cell. 2020;78(3):477-92 e8. *Equal contribution.
6	Rodriguez-Meira A, Buck G, Clark SA, Povinelli BJ, Alcolea V, Louka E, McGowan S, Hamblin A, Sousos N, Barkas N, Giustacchini A, Psaila B, Jacobsen SEW, Thongjuea S, Mead AJ. Unravelling Intratumoral Heterogeneity through High-Sensitivity Single-Cell Mutational Analysis and Parallel RNA Sequencing. Molecular Cell. 2019;73(6):1292-305 e8.
7	Booth CAG, Barkas N⁺, Neo WH⁺, Boukarabila H, Soilleux EJ, Giotopoulos G, Farnoud N, Giustacchini A, Ashley N, Carrelha J, Jamieson L, Atkinson D, Bouriez-Jones T, Prinjha RK, Milne TA, Teachey DT, Papaemmanuil E, Huntly BJP, Jacobsen SEW, Mead AJ^à. Ezh2 and Runx1 Mutations Collaborate to Initiate Lympho-Myeloid Leukemia in Early Thymic Progenitors. Cancer Cell. 2018;33(2):274-91 e8.^+,* Equal contribution.^àLead corresponding author
8	Giustacchini A⁺, Thongjuea S⁺, Barkas N, Woll PS, Povinelli BJ, Booth CAG, Sopp P, Norfo R, Rodriguez-Meira A, Ashley N, Jamieson L, Vyas P, Anderson K, Segerstolpe A, Qian H, Olsson-Stromberg U, Mustjoki S, Sandberg R, Jacobsen SEW, Mead AJ. Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia. Nature Medicine*. 2017;23(6):692-702. ^+, Equal contribution.

How to apply

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

Find out more

1	Rodriguez-Meira A, Norfo, Wen S, Chédeville AL, Rahman H, O’Sullivan J, Wang G, Louka E, Kretzschmar WW, Paterson A, Brierley C, Martin J, Demeule C, Bashton M, Sousos N, Moralli D, Subha Meem L, Carrelha J, Wu B, Hamblin A, Guermouche H, Pasquier F, Marzac C, Girodon F, Vainchenker W, Drummond M, Harrison C, Chapman JR, Plo I, Jacobsen SE, Psaila B, Thongjuea S, Antony-Debré I^§, Mead AJ^§ Single-Cell Multi-Omics Identifies Chronic Inflammation as a Driver of TP53 mutant Leukaemic Evolution. Nature Genetics. 2023; in press. *equal contribution. ^§Joint corresponding authors.
2	Harrison CN, Nangalia J, Boucher R, Jackson A, Yap C, O'Sullivan J, Fox S, Ailts I, Dueck AC, Geyer HL, Mesa RA, Dunn WG, Nadezhdin E, Curto-Garcia N, Green A, Wilkins B, Coppell J, Laurie J, Garg M, Ewing J, Knapper S, Crowe J, Chen F, Koutsavlis I, Godfrey A, Arami S, Drummond M, Byrne J, Clark F, Mead-Harvey C, Baxter EJ, McMullin MF, Mead AJ. Ruxolitinib Versus Best Available Therapy for Polycythemia Vera Intolerant or Resistant to Hydroxycarbamide in a Randomized Trial. Journal of Clinical Oncology. 2023;41(19):3534-44.
3	Sousos N⁺, Ni Leathlobhair M⁺, Simoglou Karali C, Louka E, Bienz N, Royston D, Clark SA, Hamblin A, Howard K, Mathews V, George B, Roy A, Psaila B, Wedge DC, Mead AJ. In utero origin of myelofibrosis presenting in adult monozygotic twins. Nature Medicine. 2022. * Equal contribution and joint corresponding authors.
4	Louka E, Povinelli B, Rodriguez-Meira A, Buck G, Wen WX, Wang G, Sousos N, Ashley N, Hamblin A, Booth CAG, Roy A, Elliott N, Iskander D, de la Fuente J, Fordham N, O'Byrne S, Inglott S, Norfo R, Salio M, Thongjuea S, Rao A, Roberts I⁺, Mead AJ⁺. Heterogeneous disease-propagating stem cells in juvenile myelomonocytic leukemia. Journal of Experimental Medicine. 2021;218(2). ^+,* Equal contribution.
5	Psaila B, Wang G, Rodriguez-Meira A, Li R, Heuston EF, Murphy L, Yee D, Hitchcock IS, Sousos N, O'Sullivan J, Anderson S, Senis YA, Weinberg OK, Calicchio ML, Center NIHIS, Iskander D, Royston D, Milojkovic D, Roberts I, Bodine DM, Thongjuea S, Mead AJ. Single-Cell Analyses Reveal Megakaryocyte-Biased Hematopoiesis in Myelofibrosis and Identify Mutant Clone-Specific Targets. Molecular Cell. 2020;78(3):477-92 e8. *Equal contribution.
6	Rodriguez-Meira A, Buck G, Clark SA, Povinelli BJ, Alcolea V, Louka E, McGowan S, Hamblin A, Sousos N, Barkas N, Giustacchini A, Psaila B, Jacobsen SEW, Thongjuea S, Mead AJ. Unravelling Intratumoral Heterogeneity through High-Sensitivity Single-Cell Mutational Analysis and Parallel RNA Sequencing. Molecular Cell. 2019;73(6):1292-305 e8.
7	Booth CAG, Barkas N⁺, Neo WH⁺, Boukarabila H, Soilleux EJ, Giotopoulos G, Farnoud N, Giustacchini A, Ashley N, Carrelha J, Jamieson L, Atkinson D, Bouriez-Jones T, Prinjha RK, Milne TA, Teachey DT, Papaemmanuil E, Huntly BJP, Jacobsen SEW, Mead AJ^à. Ezh2 and Runx1 Mutations Collaborate to Initiate Lympho-Myeloid Leukemia in Early Thymic Progenitors. Cancer Cell. 2018;33(2):274-91 e8.^+,* Equal contribution.^àLead corresponding author
8	Giustacchini A⁺, Thongjuea S⁺, Barkas N, Woll PS, Povinelli BJ, Booth CAG, Sopp P, Norfo R, Rodriguez-Meira A, Ashley N, Jamieson L, Vyas P, Anderson K, Segerstolpe A, Qian H, Olsson-Stromberg U, Mustjoki S, Sandberg R, Jacobsen SEW, Mead AJ. Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia. Nature Medicine*. 2017;23(6):692-702. ^+, Equal contribution.