WIMM PI
Curriculum Vitae
Personal Data
Name
Nationality
Email
Irene Roberts
UK
pending
Present Position
2013-present
Honorary Consultant in Paediatric Haematology (Oxford Trust)
2013-present
Professor of Paediatric Haematology, (University of Oxford)
Previous Positions
1978
House Physician to Professor E.M. McGirr, Glasgow Royal Infirmary.
1979
House Surgeon to Mr D.H. Clark, Gartnavel General Hospital, Glasgow.
1979
SHO Obstetrics to Professor C. Whitfield, Queen Mother's Hospital, Glasgow.
1980
SHO Paediatrics to Professor F. Cockburn, Royal Hospital for Sick Children,
Glasgow.
1981
SHO/Registrar in Medicine to Dr R. Walker, Law Hospital, Lanarkshire.
1981
Registrar in Haematology to Dr R.L.C. Cumming, Stobhill Hospital, Glasgow.
1983
Research Fellow, Department of Pharmacology and Medicine, Vanderbilt University,
Nashville, Tennessee with Dr GA FitzGerald; MD (Hons) University of Glasgow.
1985
Lecturer in Haematology to Professor N.H. Russell, University of Nottingham.
Honorary Senior Registrar in Haematology, City Hospital, Nottingham.
1988
Senior Research Fellow with Professor Lucio Luzzatto, Department of Haematology,
Royal Postgraduate Medical School, London.
1990
Senior Lecturer in Paediatric Haematology, Royal Postgraduate Medical School.
Honorary Consultant Paediatric Haematologist, Hammersmith Hospital, London.
2000
Professor of Paediatric Haematology, Royal Postgraduate Medical School (now
Imperial College London).
Honorary Consultant Paediatric Haematologist Hammersmith and St Mary's
Hospitals (now Imperial College Healthcare NHS Trust), London.
Research Achievements
Over the last 20 years, we have investigated the biological basis of the high frequency of
haematological disorders which affect newborn infants. Through clinical and laboratory
studies to properly define their natural history and haematopoietic defects, we found that
most disorders originate in fetal life and are the consequence of perturbation of fetal
haematopoiesis, for example due to chronic hypoxia or antibody-mediated suppression of
progenitor development, rather than secondary to acquired post-natal events. We therefore
established a programme to characterise normal human fetal haematopoiesis and, from a
clinical point of view, to develop aetiology-based classifications of neonatal
thrombocytopenia and anaemia which simplify diagnosis/management and are now in
widespread use. In the last 5 years we have specifically focused on the cellular and
molecular basis for trisomy 21-mediated perturbation of fetal haematopoiesis and the impact
of trisomy 21 on leukaemia initiation. Through immunophenotypic, functional and gene
expression studies on isolated primary fetal haematopoietic stem/progenitor cells we have
shown that trisomy 21 itself causes abnormal development of fetal haematopoietic
progenitors and, more recently, that trisomy 21 interferes with fetal haematopoietic stem cell
function, causing a marked megakaryocyte/erythroid bias and profound impairment of B
lymphocyte development. On a clinical level the importance of trisomy-21-mediated
perturbation of fetal haematopoiesis lies with the recognised markedly increased risk of
acute leukaemia in children with Down syndrome (trisomy 21). To investigate the
pathogenesis of trisomy 21-associated acute myeloid leukaemia (AML), in collaboration with
Paresh Vyas' lab (WIMM), we established a prospective Down syndrome neonatal cohort
study to define the natural history at the clinical, haematological and molecular level. This
recently found that acquired N-terminal truncating mutations in GATA1 occur at very high
frequency (~30%) in neonates with Down syndrome. Multilineage haematopoietic
abnormalities are present in all Down syndrome neonates, further implicating trisomy 21 in
driving abnormal haematopoiesis.
What are the Future Aims of Your Current Group?
We now want to identify the molecular mechanisms which explain how the presence of 3
copies of chromosome 21 produces specific defects in fetal haematopoietic stem/progenitor
cells and, ultimately, how this contributes to leukaemogenesis in children with Down
syndrome. We will continue to work on primary human fetal cells as no mouse models or
ES/iPS models fully recapitulate the human disease. As a starting point, we will attempt to
identify consistent differences in the gene expression patterns in highly purified
haematopoietic stem and progenitor populations from normal and trisomy 21 fetal liver.
Initially we expect to focus on differences where expression of chromosome 21 genes is
likely to be implicated. Overexpression and knockdown studies in primary cells will be used
to test the functional significance of these changes. The role of the trisomy 21
microenvironment will be investigated directly (through gene expression of trisomic and
disomic fetal liver stromal cells) and indirectly by investigating the effects of trisomy 21 on
primary human fetal bone marrow haematopoietic stem and progenitor cells using similar
approaches to our previous work in fetal liver. These studies will also be used to investigate
the molecular basis of increased susceptibility of children with Down syndrome to B lineage
acute lymphoblastic leukaemia and immune deficiency. In collaboration with Paresh Vyas'
lab, data and samples from the Down Syndrome Neonatal Cohort Study will be used to
identify the clinical, haematological and molecular characteristics that predict transformation
of the neonatal preleukaemic condition TAM, to overt acute myeloid leukaemia. As part of
this we plan to measure the kinetics of regression and/or evolution of mutant GATA1 clones
following a diagnosis of TAM and the acquisition of additional genetic events in those that
transform.
How do These Aims Contribute to the Understanding and/or Management of Human
Disease
The work of my group stems directly from clinical observations made from the neonatal
haematology diagnostic service established at Hammersmith Hospital just over 20 years ago.
Integration of clinical, haematological and biological findings led to the work on human fetal
haematopoiesis as a way of interrogating the mechanism of a number of clinical
haematology problems presenting in the neonatal period. The research programme on
trisomy 21-mediated perturbation of fetal haematopoiesis and leukaemogenesis sprang
directly from this approach. Findings from the fetal studies have informed the prospective
clinical study in neonates with Down syndrome allowing the role played by trisomy 21 at
different stages of development to be captured and investigated in detail. Similarly, the
neonatal study allows the clinical, haematological and molecular evolution of the neonatal
preleukaemic disorder TAM to acute myeloid leukaemia of Down syndrome (ML-DS) to be
studied simultaneously. In this way TAM/ML-DS represents a tractable model of childhood
AML which provides a unique opportunity to investigate the cellular, genetic and epigenetic
events which occur at each stage. The ultimate aim would be to use this information to
accurately determine which children with Down syndrome will develop ML-DS and to
effectively intervene in the transformation process to actively prevent the development of
leukaemia using minimally toxic, targeted therapy. Increased understanding of how trisomy
21 transforms haematopoietic cells in children with Down syndrome may also provide insight
into acute leukaemia in children without Down syndrome (given that trisomy 21 is the
commonest acquired chromosomal anomaly in these leukaemias) and into the impact of
aneuploidy on cell growth and differentiation in cancer in general. These translational
programmes are shared between our laboratory and that of Professor Paresh Vyas.
Lay Summary of Research
We are investigating why children with Down syndrome have a much higher risk of
developing leukaemia than other children of the same age. There is now considerable
evidence that the culprit in this association with leukaemia is the extra copy of chromosome
21 (trisomy 21) which is present in every cell of the body in Down syndrome. This extra
chromosome 21 disrupts the normal functioning of blood cells in particular. We know that
this happens very early in life. Indeed, trisomy 21 interferes with blood development even
before birth. Normally there is a well regulated system which ensures balanced production of
all blood cell types. This balanced production of red blood cells, white blood cells and
platelets is dramatically disturbed in Down syndrome. The disturbance sets the scene for the
development of a unique transient leukaemia in newborn babies (known as Transient
Abnormal Myelopoiesis; TAM) and for a full blown acute leukaemia in young children with
Down syndrome which is termed Myeloid Leukaemia of Down syndrome. We also know that
trisomy 21 interferes with the development of another subset of white blood cells (the
lymphoid system). We think that the abnormalities in production of lymphoid cells caused by
trisomy 21 help to explain the problems children with Down syndrome have with infection
and why later on they may develop acute 'lymphoid' leukaemias. Our work in the lab has 2
main aims. Our first aim is to understand how trisomy 21 interferes with the genes and
proteins which control blood production early in life. We are doing this through a combination
of studies in the lab and in the clinic. The second aim is to use this information to help
design treatment to identify children with Down syndrome at risk of developing leukaemia
and design treatment strategies which reduce this risk.
All Publications Over the Past 5 Years
Patterson S, Chaidos A, Neville DC, Poggi A, Butters TD, Roberts IAG, Karadimitris A.
Human invariant NKT cells display alloreactivity instructed by invarIant TCR-CD1d
interaction and killer Ig receptors. J Immunol. 2008;181:3268-76. (5.5)
Tunstall-Pedoe O, Roy A, Karadimitris A, de la Fuente J, Fisk NM, Bennett P, Norton A,
Vyas P, Roberts I. Abnormalities in the myeloid progenitor compartment in Down
syndrome fetal liver precede acquisition of GATA1 mutations. Blood. 112, (2008),
4507-11. (10.5)
Pinto FO, Roberts I. Cord blood stem cell transplantation for haemoglobinoapthies. Br J
Haematol 141, (2008), 309-324. (4.5)
Roberts I, Murray NA. Neonatal thrombocytopenia. Sem Fetal Neonat Med 13, (2008), 256264. (3.5)
Roberts IAG. The changing face of haemolytic disease of the newborn. Early Hum Dev 84,
(2008), 515-523. (2.0)
Roberts I, Stanworth S, Murray NA. Thrombocytopenia in the neonate. Blood Rev 22,
(2008), 173-186. (6.0)
Roberts I, de la Fuente J: Hematopoietic stem cell transplantation for hemoglobinopathies.
In: Hematopoietic Stem Cell Transplantation in Clinical Practice. Eds AJ Barrett, J
Treleaven, Elsevier, 2008.
Stanworth SJ, Clarke P, Watts T, Ballard S, Choo L, Morris T, Murphy MF, Roberts I;
Platelets and Neonatal Transfusion Study Group. Proospective, observational study
of outcomes in neonates with severe thrombocytopenia. Pediatrics 124, (2009),
e826-3834. (5.1)
Trompeter S, Roberts I. Haemoglobin F modulation in childhood sickle cell disease.
Br J Haematol. 144, (2009), 308-16. (4.5)
Roy A, Roberts I, Norton A, Vyas P. Acute megakaryoblastic leukaemia (AMKL) and
transient myeloproliferative disorder (TMD) in Down syndrome: a multistep model of
leukaemogenesis. Br J Haematol 147, (2009), 3-12. (4.5)
Roberts IAG: Prenatal and childhood transfusions. In: Practical Transfusion Medicine 3rd
edition; Ch 26, pages 285-307; Editors: Murphy and Pamphilon, Blackwell, London,
2009.
Roberts I, Chakravorty S: Haematological Disorders. In: Illustrated Textbook of Paediatrics;
4th edition; Chapter 22, pages 363-385; Ed Lissauer T, Clayden G, Elsevier. 2009.
Alford K, Slender A, Vanes L, Li Z, Fisher ECM, Nizetic D, Orkin SH, Roberts I, and
Tybulewicz VLJ: Perturbed hematopoiesis in the Tc1 mouse model of Down
Syndrome. Blood (2010) 115: 2928-37. (10.5)
Halsey C, Tunstall O, Gibson B, Roberts I, Graham G. Role of GATA-1s in early
hematopoiesis and differences between alternative splicing in human and murine
GATA-1. Blood 115, (2010), 3415-6. (10.5)
Johnson MC, Kirkham FJ, Redline S, Rosen CL, Yan Y, Roberts I, Gruenwald J, Marek J,
DeBaun MR. Left ventricular hypertrophy and diastolic dysfunction in children with
sickle cell disease are related to asleep and waking oxygen desaturation. Blood 116,
(2010), 16-21. (10.5)
Clarke SA, Skinner R, Guest J, Darbyshire P, Cooper J, Shah F, Roberts I, Eiser C. Healthrelated quality of life and financial impact of caring for a child with Thalassaemia
Major in the UK. Child Care Health Dev 36, (2010), 118-122.
Ng GY, Roberts I, New HV. Exchange transfusion and intravenous immunoglobulin use in
the UK. Arch Dis Child 95, (2010), F6-F7. (3.5)
Walters MC, Hardy K, Edwards S, Adamkiewicz T, Barkovich J, Bernaudin F, Buchanan GR,
Bunin N, Dickerhoff R, Giller R, Haut PR, Horan J, Hsu LL, Kamani N, Levine JE,
Margolis D, Ohene-Frempong K, Patience M, Redding-Lallinger R, Roberts I,
Rogers ZR, Sanders JE, Scott JP, Sullivan KM; Multicenter study of bone marrow
transplantation for sickle cell disease. Pulmonary, gonadal and central nervous
system status after bone marrow transplantation for sickle cell disease. Biol Bone
Marrow Transplant 16, (2010), 263-272. (3.7)
Roberts I, de Montalembert M. Sickle cell disease: primum non nocere (first do no harm).
Haematologica 95, (2010), 4-5. (6.0)
Hu M, Bassett JH, Danks L, Howell PG, Xu K, Spanoudakis E, Kotsianidis I, Boyde A,
Williams GR, Horwood N, Roberts IAG, Karadimitris A. Activated invariant NKT cells
regulate osteoclast development and function. J Immunol. 186, (2011), 2910-7. (5.5)
Alford KA, Reinhardt K, Garnett C, Norton A, Böhmer K, von Neuhoff C, Kolenova A, Marchi
E, Klusmann JH, Roberts I, Hasle H, Reinhardt D, Vyas P. Analysis of GATA1
mutations in Down syndrome transient myeloproliferative disorder and myeloid
leukemia. Blood 118, (2011), 2222-2238. (10.5)
Roberts I, Vyas P. Enigmatic variation. Blood 118, (2011), 6723-6724. (10.5)
Zhang EG, Regan F, Layton M, Paramasivam G, Wyatt-Ashmead J, Roberts I, Kumar S.
Managing the difficult case of fetal anemia. J Matern Fetal Neonatal Med 24, (2011),
1498-1503.
Roberts I, Chakravorty S: Haematology. In : Neonatology at a Glance. 2nd edition; Ch 6
and Ch 7, pages 82-83; 132-137; Eds Lissauer T, Fanaroff AA. Blackwell, London,
2011.
Chaidos A, Patterson S, Szydlo R, Chaudhry S, Dazzi F, Kanfer E, Macdonald D, Marin D,
Milojkovic D, Pavlu J, Davis J, Rahemtulla A, Rezvani K, Goldman J, Roberts I,
Apperley J, Karadimitris A. Graft invariant natural killer T-cell dose predicts risk of
acute graft versus host disease in allogeneic hematopoietic stem cell transplantation.
Blood 119, (2012), 5030-6. (10.5)
Roy, A*, Cowan G*, Mead AJ, Filippi S, Bohn G, Chaidos A, Tunstall O, Chan JKY, Choolani
M, Bennett P, Kumar S, Atkinson D, Wyatt-Ashmead J, Hu M, Stumpf M, Chou ST,
Weiss MJ, Karadimitris A, Jacobsen SE, Vyas P, Roberts I. Perturbation of fetal liver
hematopoietic stem and progenitor development by trisomy 21. Proc Natl Acad Sci
USA 109, (2012). 17579-84. (9.3)
Muthukumar P, Venkatesh V, Curley A, Cahan BC, Choo L, Ballard S, Clarke P, Watts T,
Roberts I, Stanworth S; Platelets Neonatal Transfusion Study Group. Severe
thrombocytopenia and patterns of bleeding in neonates: results from a prospective
observational study and implications for use of platelet transfusion. Transfus Med
22, (2012), 338-343.
Psaila B, Lyden D, Roberts I. Megakaryocytes, malignancy and bone marrow vascular
niches. J Thromb Haemost 10, (2012), 177-188. (6.1)
Chakravorty, Roberts I: How I manage neonatal thrombocytopenia. Br J Haematol 156,
(2012), 155-162. (4.5)
Roy A, Roberts I, Vyas P. Biology and management of transient abnormal myelopoiesis
(TAM) in children with Down syndrome. Semin Fetal Neonatal Med 17, (2012), 196201. (3.5)
Mullins E, Prior T, Roberts I, Kumar S. Changes in the fetal and neonatal cytokine profile in
pregnancies complicatied by intrauterine growth restriction. Am J Reprod Immunol 69
(2013), 441-448.
Chaidos A, Barnes C, Cowan G, May P, Melo V, Hatjiharissi E, Papaioannou M, Harrington
H, Doolittle H, Terpos E, Abdalla S, Yarranton H, Naresh K, Foroni L, Reid A,
Rahemtulla A, Stumpf M, Roberts I, Karadimitris A: Clinical drug resistance linked to
inter-convertible phenotypic and functional states of tumor propagating cells in
multiple myeloma. Blood 121, (2013), 318-328. (10.5)
Roy A, Cowan G, Vyas P, Roberts I. The impact of trisomy 21 on early human
hematopoiesis. Cell Cycle 12, (2013), 533-34. (4.1)
Gargiulo L, Papaioannou M, Sica M, Talini G, Chaidos A, Richichi B, Nikolaev AV, Nativi C,
Layton M, de la Fuente J, I Roberts, Luzzatto L, Notaro R, Karadimitris A.
Glycosylphosphatidylinositol-specific, CD1d-restricted T cells in paroxysmal
nocturnal hemoglobinuria. Blood 121, (2013), 2753-61. (10.5)
Caputo V, Costa JR, Makarona K, Georgiou E, Layton M, Roberts I, Karadimitris A.
Dissection of a functional hierarchy that determines Polycomb recruitment to CpG
islands as revealed by inherited disease-associated mutation. Hum Mol Genet 22
(2013), 3187-94. (7.8)
Gerrard G, Volganon M, Foong HE, Kasperaviciute D, Iskander D, Game L, Muller M,
Aitman TJ, Roberts I, de la Fuente J, Foroni L, Karadimitris A. Target enrichment
and high-throughput sequencing of 80 ribosomal protein genes to identify mutations
associated with Diamond-Blackfan anaemia. Br J Haematol 162 (2013), 530-36. (4.5)
Locatelli F, Kabbara NN, Ruggeri A, Ghavamzadeh A, Roberts I, Li CK, Bernaudin F,
Vermylen C, Dalle JH, Stein J, Wynn R, Cordonnier C, Pinto F, Angelucci E, Socie
G,
Gluckman E, Walters M, and Rocha V. Outcome of patients with
haemoglobinopathies given either cord blood or bone marrow transplantation from an
HLA-identical sibling. Blood 122 (2013), 1072-78. (10.5)
Innes AJ, Beattie R, Sergeant R, Ghandi D, Foroni L, Marin D, Kanfer E, Mielke S, Milojkovic
D, Macdonald D, Pavlu J, Rahemtulla A, Roberts I, Slade D, Bray E, Goldman J,
Apperley J, Szydlo R, Dazzi F, Rezvani K. Escalating-dose HLA-mismatched DLI is
safe for the treatment of leukaemia relapse following alemtuzumab-based
myeloablative allo-SCT. Bone Marrow Transplant (2013) Epub May 20 (3.5)
Roberts I, Luban N, New HV: Fetal, neonatal and childhood transfusions. In: Practical
Transfusion Medicine 3rd edition; Chapter 32; pages 347-367. Editors: Murphy and
Pamphilon, Blackwell, London, 2013.
Roberts IAG, Chakravorty S: Thrombocytopenia in the newborn. In: Platelets Third Edition;
Chapter 45, pages 929-951; Editor: Michelson A, Academic Press, New York, 2013.
Roberts, I, Alford K, Hall G, Juban G, Richmond H, Norton A, Vallance G, Marchi E,
McGowan S, Roy A, Cowan G, Anthony M, Gupta A, Ho J, Uthaya S, Curley A,
Rasiah VS, Watts T, Nicholl R, Bedford-Russell A, Blumberg R, Thomas A, Gibson
B, Halsey C, Lee PW, Godambe S, Sweeney C, Perkins K, Bhatnagar N, Goriely A,
Campbell P, Vyas P; Oxford-Imperial Down Syndrome Cohort Study Group. GATA1
mutant clones are frequent and often unsuspected in babies with Down syndrome:
identification of a population at risk of leukemia. Blood (in press). (10.5)
Roberts I, O'Connor D, Roy A, Cowan G, Vyas P. The impact of trisomy 21 on fetal
haematopoiesis. Blood Cells Mol Dis (2013) Epub (2.3)
Roberts IAG, Murray NA: Haematology. In: Roberton's Textbook of Neonatology 5th edition;
Chapter 30; Editor: JM Rennie, Churchill Livingstone, London (in press).
Roberts I, Chakravorty S: Neonatal thrombocytopenia. In: Pediatric and Adolescent
Hematology: Controversies and Advances in Management. Editors: A Thomas and C
Halsey. Karger AG, Basel, Switzerland (in press).
Ten Key Publications Throughout your Career
Knapp HR, Reilly IAG, Alessandrini P, FitzGerald GA: In vivo indexes of platelet and
vascular function during fish oil administration in patients with atherosclerosis. New
Engl J Med 314, (1986), 937-942.
Reilly IAG, FitzGerald GA: Inhibition of thromboxane formation in vivo and ex vivo:
implications for therapy with platelet inhibitory drugs. Blood 69, (1987), 180-186.
Reilly IAG, Kozlowski R, Russell NH: Heterogeneous mechanisms of autocrine growth of
AML blasts. Br J Haematol 72, (1989), 363-369.
Rieux-Laucat F, Le Deist F, Hivroz C, Roberts IAG, Debatin KM, Fischer A, de Villartay JP:
Apo-1/ Fas/ CD95 mutations in human lymphoproliferative syndrome associated with
autoimmunity and defective apoptosis. Science 248, (1995) 1347-1349.
Maher J, Baker DA, Manning M, Dibb NJ, Roberts IAG: Evidence for cell-specific
differences in transformation by N-ras, K-ras and H-ras. Oncogene 11, (1995), 16391647.
Vaughan JI, Manning M, Warwick RM, Letsky E, Murray NA, Roberts IAG: Inhibition of
erythroid progenitor cell growth by anti-Kell (K): a mechanism for fetal anemia in Kimmunized pregnancies New Engl J Med 338, (1998), 798-803.
Campagnoli C, Fisk NM, Bennett P, Overton T, Watts TL, Roberts IAG. Circulating
hematopoietic cells in first trimester fetal blood. Blood 95, (2000), 1967-72.
Tunstall-Pedoe O, Roy A, Karadimitris A, de la Fuente J, Fisk NM, Bennett P, Norton A,
Vyas P, Roberts I. Abnormalities in the myeloid progenitor compartment in Down
syndrome fetal liver precede acquisition of GATA1 mutations. Blood. 112, (2008),
4507-11.
Roy, A*, Cowan G*, Mead AJ, Filippi S, Bohn G, Chaidos A, Tunstall O, Chan JKY, Choolani
M, Bennett P, Kumar S, Atkinson D, Wyatt-Ashmead J, Hu M, Stumpf M, Chou ST,
Weiss MJ, Karadimitris A, Jacobsen SE, Vyas P, Roberts I. Perturbation of fetal liver
hematopoietic stem and progenitor development by trisomy 21. Proc Natl Acad Sci
USA 109, (2012). 17579-84.
Roberts, I, Alford K, Hall G, Juban G, Richmond H, Norton A, Vallance G, Marchi E,
McGowan S, Roy A, Cowan G, Anthony M, Gupta A, Ho J, Uthaya S, Curley A,
Rasiah VS, Watts T, Nicholl R, Bedford-Russell A, Blumberg R, Thomas A, Gibson
B, Halsey C, Lee PW, Godambe S, Sweeney C, Perkins K, Bhatnagar N, Goriely A,
Campbell P, Vyas P; Oxford-Imperial Down Syndrome Cohort Study Group. GATA1
mutant clones are frequent and often unsuspected in babies with Down syndrome:
identification of a population at risk of leukemia. Blood (in press).
Markers of Esteem
1994
FRCP
1997
FRCPath
2005
FRCPCH
2004
Appointed to the Executive Board, European Hematology Association
2010
Congress President, 16th Annual Congress of the European Hematology Association
2011
Hugh Jolly Lecture
Current Grant Support
LLR Programme Grant 2008-2013; renewal 2013-2018 (with Paresh Vyas); £1.03M, £1.4M
LLR Clinical Research Fellowship 2013-2016 (with Anastasios Karadimitris); £222K
Children with Cancer 2012-2014 (with P Vyas, A Karadimitris); £194K
Kay Kendall Leukaemia Fund Clinical Research Fellowship 2011-2014; £219K
Leuka/KKLF Clinical Research Fellowship 2012-2014; £127K
MRC 2011-2014 (PI Michael Stumpf); £20K (total £309.5K)
Wellcome Clinical PhD Fellowship 2011-2014 (with A Karadimitris): £251K