Faculty of Biological Sciences

Dr Edwin Chen

BSc, McGill University; PhD, University of Toronto
University Academic Fellowship in Molecular Mechanisms of Cancer Biology
School of Molecular and Cellular Biology

Background: Postdoctoral training: University of Cambridge (2007-2012), Harvard University (2012-2015)

Contact:  Garstang 9.57d, +44(0) 113 34 33162, email address for  

You can read more about Dr Chen's interests here:
www.edwinchenlab.com

The long-term goal of our research is to understand the molecular pathways that control the clonal evolution of leukaemic stem cells in human haematological malignancies, with a specific focus on aberrant JAK/STAT signalling. For these studies, we predominantly focus on a class of human cancers called the chronic myeloproliferative neoplasms (MPN), which harbour mutations that activate JAK/STAT pathways and provide a window into early stages of tumorigenesis that are often inaccessible in other cancers. To date, our work has illuminated mechanisms whereby aberrant JAK/STAT pathways influence diverse aspects of cell function, including DNA replication and repair, lineage fate choice and immune activity. We hope to apply these insights to the development of novel and non-toxic therapies that may prevent clonal evolution and disease progression.

Genomic instability in myeloid malignancies

Erosion of DNA repair competency accelerates clonal evolution, promotes chemotherapy resistance and correlates with poorer prognosis. However, how and why genome instability arises in some tumours remains unclear. This question of how genome instability arises during malignant transformation is often difficult to parse because genome integrity pathways are frequently already heavily compromised at disease diagnosis (eg. P53 loss). In contrast, MPN can provide a paradigm into how genome stability is regulated in a nascent neoplasm. Our previous work has shown that oncogenic non-receptor tyrosine kinases such as the JAK2V617F mutation commonly found in patients with myeloproliferative disorders causes stalling of replication forks during S-phase to engender a cellular state known as “replication stress”. Stalled replication forks are potentially mutagenic and can form DNA double-strand breaks and chromosomal rearrangements if improperly resolved. We have recently shown that RECQ helicases play a crucial role in maintaining genome integrity associated with oncogene-induced replication stress in chronic-phase disease. We have also identified subsets of patients whom are incapable of responding effectively to replication stress characterised by an inability to activate the checkpoint kinase CHK1. By analysing the transcriptional and mutational profiles of these patients, we have begun to dissect the pathways crucial for DNA repair that are subverted during leukaemic progression.

Calreticulin mutations in myeloproliferative neoplasms

In 2003, somatic mutations in the gene CALR was identified in ~30% of patients with the MPN subtypes essential thrombocythaemia (ET) and primary myelofibrosis (MF). CALR encodes a calcium-dependent ER-resident chaperone called calreticulin, and represents the first time that this class of proteins has been implicated in cancer. CALR mutations are mutually exclusive with other MPN lesions that activate JAK/STAT pathways (including JAK2V617F and MPLW515L), and gives rise to an alternative reading frame that encodes a mutation-specific novel C-terminal tail of calreticulin. However, the mechanism by which these mutations can promote MPN development remains unknown. In collaboration with the Astbury Centre for Structural Molecular Biology, we are undertaking a wide array of structural biology techniques to interrogate the impact of these mutations on the structure and function of the calreticulin protein. In particular, we are interested in the impact of CALR mutations on JAK/STAT activation and megakaryopoiesis. These insights may enable us to gain a deeper understanding into the biology behind these mutations and their role in MPN pathogenesis. 

 

Studentships information

Undergraduate project topics:

  • Investigation of mutant calreticulin structure by NMR
  • Molecular mechanism of action of mutant calreticulin in JAK/STAT activation
  • Development of CRISPR/Cas9 technology as a genomic locus tracking tool

Postgraduate project areas:

  • Molecular regulation of CHK1 activity during leukaemogenesis
  • Genomic and proteomic characterisation of cancer-specific R-loops
 

Faculty Research and Innovation

Modules taught

BIOC3160 - Laboratory/Literature/Computing Research Project
BIOC3221/22/BIOL3210/MICR3211 C - ATU - Haematological cancers
BIOL2111/BIOC2301 - Integrated Biochemistry/Genetic Engineering
BIOL3306 - Biological Sciences Research Project
BIOL5294M - MSc Bioscience Research Project Proposal
BIOL5382M - Extended Research Project
BIOL5392M - Bioscience MSc Research Project
FOBS1201/BIOL1214 - Molecular Physiology/Multicellular Systems

Group Leader Dr Edwin Chen  (University Academic Fellowship in Molecular Mechanisms of Cancer Biology)

Miss Rajni Mehta  (Research Technician)

Postgraduates

Rajni Bhardwaj (Primary supervisor) 75% FTE
Dominic Lowen (Primary supervisor) 34% FTE
Jeanne Rivera (Primary supervisor) 50% FTE
. Lalchungnunga (Co-supervisor) 40% FTE
Laura Warwick (Co-supervisor) 33% FTE

Ahn JS, Li J, Chen E, Kent DG, Park HJ, Green AR JAK2V617F mediates resistance to DNA damage-induced apoptosis by modulating FOXO3A localization and Bcl-xL deamidation. Oncogene 35 2235-2246, 2016
DOI:10.1038/onc.2015.285
View abstract

Elf S, Abdelfattah NS, Chen E, Perales-Patón J, Rosen EA, Ko A, Peisker F, Florescu N, Giannini S, Wolach O, Morgan EA, Tothova Z, Losman J-A, Schneider RK, Al-Shahrour F, Mullally A Mutant Calreticulin Requires Both Its Mutant C-terminus and the Thrombopoietin Receptor for Oncogenic Transformation. Cancer Discov 6 368-381, 2016
DOI:10.1158/2159-8290.CD-15-1434
View abstract

Schneider RK, Schenone M, Ferreira MV, Kramann R, Joyce CE, Hartigan C, Beier F, Brümmendorf TH, Germing U, Platzbecker U, Büsche G, Knüchel R, Chen MC, Waters CS, Chen E, Chu LP, Novina CD, Lindsley RC, Carr SA, Ebert BL Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8 and S100A9. Nature medicine 22 288-297, 2016
DOI:10.1038/nm.4047
View abstract

Godfrey AL, Chen E, Massie CE, Silber Y, Pagano F, Bellosillo B, Guglielmelli P, Harrison CN, Reilly JT, Stegelmann F, Bijou F, Lippert E, Boiron JM, Döhner K, Vannucchi AM, Besses C, Green AR STAT1 activation in association with JAK2 exon 12 mutations. Haematologica 101 e15-e19, 2016
DOI:10.3324/haematol.2015.128546

Chen E, Ahn JS, Sykes DB, Breyfogle LJ, Godfrey AL, Nangalia J, Ko A, DeAngelo DJ, Green AR, Mullally A RECQL5 Suppresses Oncogenic JAK2-Induced Replication Stress and Genomic Instability. Cell reports 13 2345-2352, 2015
DOI:10.1016/j.celrep.2015.11.037
View abstract

Tapper W, Jones AV, Kralovics R, Harutyunyan AS, Zoi K, Leung W, Godfrey AL, Guglielmelli P, Callaway A, Ward D, Aranaz P, White HE, Waghorn K, Lin F, Chase A, Baxter EJ, Maclean C, Nangalia J, Chen E, Evans P, Short M, Jack A, Wallis L, Oscier D, Duncombe AS, Schuh A, Mead AJ, Griffiths M, Ewing J, Gale RE, Schnittger S, Haferlach T, Stegelmann F, Döhner K, Grallert H, Strauch K, Tanaka T, Bandinelli S, Giannopoulos A, Pieri L, Mannarelli C, Gisslinger H, Barosi G, Cazzola M, Reiter A, Harrison C, Campbell P, Green AR, Vannucchi A, Cross NC Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms. Nature communications 6 6691-, 2015
DOI:10.1038/ncomms7691
View abstract

Chen E, Schneider RK, Breyfogle LJ, Rosen EA, Poveromo L, Elf S, Ko A, Brumme K, Levine R, Ebert BL, Mullally A Distinct effects of concomitant Jak2V617F expression and Tet2 loss in mice promote disease progression in myeloproliferative neoplasms. Blood 125 327-335, 2015
DOI:10.1182/blood-2014-04-567024
View abstract

Chen E, Mullally A How does JAK2V617F contribute to the pathogenesis of myeloproliferative neoplasms? Hematology 2014 268-276, 2014
DOI:10.1182/asheducation-2014.1.268
View abstract

Chen E, Ahn JS, Massie CE, Clynes D, Godfrey AL, Li J, Park HJ, Nangalia J, Silber Y, Mullally A, Gibbons RJ, Green AR JAK2V617F promotes replication fork stalling with disease-restricted impairment of the intra-S checkpoint response. Proceedings of the National Academy of Sciences of the United States of America 111 15190-15195, 2014
DOI:10.1073/pnas.1401873111
View abstract

Li J, Kent DG, Godfrey AL, Manning H, Nangalia J, Aziz A, Chen E, Saeb-Parsy K, Fink J, Sneade R, Hamilton TL, Pask DC, Silber Y, Zhao X, Ghevaert C, Liu P, Green AR JAK2V617F homozygosity drives a phenotypic switch in myeloproliferative neoplasms, but is insufficient to sustain disease. Blood 123 3139-3151, 2014
DOI:10.1182/blood-2013-06-510222
View abstract

Godfrey AL, Chen E, Pagano F, Silber Y, Campbell PJ, Green AR Clonal analyses reveal associations of JAK2V617F homozygosity with hematologic features, age and gender in polycythemia vera and essential thrombocythemia. Haematologica 98 718-721, 2013
DOI:10.3324/haematol.2012.079129
View abstract

Godfrey AL, Chen E, Pagano F, Ortmann CA, Silber Y, Bellosillo B, Guglielmelli P, Harrison CN, Reilly JT, Stegelmann F, Bijou F, Lippert E, McMullin MF, Boiron J-M, Döhner K, Vannucchi AM, Besses C, Campbell PJ, Green AR JAK2V617F homozygosity arises commonly and recurrently in PV and ET, but PV is characterized by expansion of a dominant homozygous subclone. Blood 120 2704-2707, 2012
DOI:10.1182/blood-2012-05-431791
View abstract

Chen E, Staudt LM, Green AR Janus kinase deregulation in leukemia and lymphoma. Immunity 36 529-541, 2012
DOI:10.1016/j.immuni.2012.03.017
View abstract

Li J, Kent DG, Chen E, Green AR Mouse models of myeloproliferative neoplasms: JAK of all grades. Dis Model Mech 4 311-317, 2011
DOI:10.1242/dmm.006817
View abstract

Chen E, Beer PA, Godfrey AL, Ortmann CA, Li J, Costa-Pereira AP, Ingle CE, Dermitzakis ET, Campbell PJ, Green AR Distinct clinical phenotypes associated with JAK2V617F reflect differential STAT1 signaling. Cancer Cell 18 524-535, 2010
DOI:10.1016/j.ccr.2010.10.013
View abstract

Li J, Spensberger D, Ahn JS, Anand S, Beer PA, Ghevaert C, Chen E, Forrai A, Scott LM, Ferreira R, Campbell PJ, Watson SP, Liu P, Erber WN, Huntly BJP, Ottersbach K, Green AR JAK2 V617F impairs hematopoietic stem cell function in a conditional knock-in mouse model of JAK2 V617F-positive essential thrombocythemia. Blood 116 1528-1538, 2010
DOI:10.1182/blood-2009-12-259747
View abstract

Beer PA, Delhommeau F, LeCouédic JP, Dawson MA, Chen E, Bareford D, Kusec R, McMullin MF, Harrison CN, Vannucchi AM, Vainchenker W, Green AR Two routes to leukemic transformation after a JAK2 mutation-positive myeloproliferative neoplasm. Blood 115 2891-2900, 2010
DOI:10.1182/blood-2009-08-236596
View abstract

Wood AD, Chen E, Donaldson IJ, Hattangadi S, Burke KA, Dawson MA, Miranda-Saavedra D, Lodish HF, Green AR, Göttgens B ID1 promotes expansion and survival of primary erythroid cells and is a target of JAK2V617F-STAT5 signaling. Blood 114 1820-1830, 2009
DOI:10.1182/blood-2009-02-206573
View abstract

Chen E, Kwon YT, Lim MS, Dubé ID, Hough MR Loss of Ubr1 promotes aneuploidy and accelerates B-cell lymphomagenesis in TLX1/HOX11-transgenic mice. Oncogene 25 5752-5763, 2006
DOI:10.1038/sj.onc.1209573
View abstract

Chen E, Lim MS, Rosic-Kablar S, Liu J, Jolicoeur P, Dubé ID, Hough MR Dysregulated expression of mitotic regulators is associated with B-cell lymphomagenesis in HOX11-transgenic mice. Oncogene 25 2575-2587, 2006
DOI:10.1038/sj.onc.1209285
View abstract