Professor Irene Roberts

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 IAG, Rogers ZR, Sanders JE, Scott JP, Sullivan KMet al., 2010, Pulmonary, Gonadal, and Central Nervous System Status after Bone Marrow Transplantation for Sickle Cell Disease, BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION, Vol: 16, Pages: 263-272, ISSN: 1083-8791

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• Citations: 136

Ng GYT, Roberts I, New HV, 2010, Exchange transfusion and intravenous immunoglobulin use in the UK, ARCHIVES OF DISEASE IN CHILDHOOD-FETAL AND NEONATAL EDITION, Vol: 95, Pages: F76-F77, ISSN: 1359-2998

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de Montalembert M, Roberts I, 2010, Sickle cell disease: <i>primum non nocere</i> (first do no harm), HAEMATOLOGICA-THE HEMATOLOGY JOURNAL, Vol: 95, Pages: 4-6, ISSN: 0390-6078

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• Citations: 4

Roy A, Cowan G, Bohn G, Hu M, Tunstall-Pedoe O, Ehsanulla N, Chan J, Mattar C, Bennett P, Vyas P, Karadimitris A, Roberts Iet al., 2010, Bone marrow haematopoiesis in the second trimester of fetal life is strongly biased towards B-lymphopoiesis and is severely impaired at the EBP-CBP transition in Down syndrome, European Haematology Association

Background: Children with Down syndrome (DS;trisomy 21;T21) have increased susceptibility to autoimmune disease and lymphopenia-associated infection as well as a 12-fold increased risk of B-acute lymphoblastic leukaemia (ALL), while T-ALL is rare, suggesting that T21 may specifically perturb B-lineage development. While acute myeloid leukaemia in DS children is characterised by an identifiable 'pre-leukaemic' phase with prenatal acquisition of GATA1 mutations which is preceded by expansion of fetal liver megakaryocyte-erythroid progenitors, DS-ALL does not present neonatally and a similar 'pre-leukaemic' phase has not been identified. Our lab recently showed that T21 itself causes increased self-renewal of CMP and strongly biases their differentiation towards the megakaryocyte-erythroid lineage. Aim: To test the hypothesis that T21 perturbs B-lymphopoiesis.Methods: We analysed B-lymphoid progenitors in fetal liver, bone marrow (BM) and cord blood (CB) in DS compared to disomic controls. Results: B-cell progenitors (BCP) at all differentiation stages were detectable in normal second trimester fetal liver where they formed 16.6+1% of the total CD34+ population. The majority of normal fetal liver BCP were committed BCP (CD34int-loCD19+;10.6+1.6% of CD34+ cells) with a lower frequency of early B progenitors (EBP;CD34hiCD127+CD19negCD10neg;5.1+1.1% of CD34+). By contrast, in DS fetal liver, BCP frequency and numbers were severely reduced (4.0+1.3% of CD34+) with particular reduction in committed BCP (CD34int-loCD19+;0.7+0.25%) and relative preservation of EBP (2.4+1.1%) which was recapitulated by in vitro differentiation on OP9-stroma. By comparison with normal fetal liver, BCP were present in large numbers in normal second trimester fetal BM where they formed 51.1+3.4% of CD34+ cells. Although all stages of BCP were present in second trimester BM, EBP formed 4.9+1% of CD34+ and most BCP (45.1+4%) were committed CD19+BCP. Similar to DS fetal liver, BCP in second trimes

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Psaila B, Podolanczuk A, Lavotshkin S, Lawrence J, Kaplan R, Granitto S, Bussel JB, Kikkeri N, Roberts I, Lyden Det al., 2009, Interactions Between Megakaryocytes and Tumour Cells at the Bone Marrow Vascular Stem Cell Niche Promote Tumour Growth and Metastasis, 51st Annual Meeting of the American-Society-of-Hematology, Publisher: AMER SOC HEMATOLOGY, Pages: 194-194, ISSN: 0006-4971

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Stanworth SJ, Clarke P, Watts T, Ballard S, Choo L, Morris T, Murphy MF, Roberts Iet al., 2009, Prospective, Observational Study of Outcomes in Neonates With Severe Thrombocytopenia, PEDIATRICS, Vol: 124, Pages: E826-E834, ISSN: 0031-4005

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• Citations: 107

Trompeter S, Roberts I, 2009, Haemoglobin F modulation in childhood sickle cell disease, BRITISH JOURNAL OF HAEMATOLOGY, Vol: 144, Pages: 308-316, ISSN: 0007-1048

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• Citations: 19

Gavlak JCD, Johnson U, Roberts I, Wilkey O, Roberts-Harewood M, Yardumian A, Laverty A, Lane R, Kirkham FJet al., 2009, Sleep disordered breathing and transcranial Doppler in sickle cell anaemia, 49th Annual Scientific Meeting of the British-Society-for-Haematology, Publisher: WILEY-BLACKWELL PUBLISHING, INC, Pages: 46-46, ISSN: 0007-1048

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Roy A, Roberts I, Norton A, Vyas Pet al., 2009, Acute megakaryoblastic leukaemia (AMKL) and transient myeloproliferative disorder (TMD) in Down syndrome: a multi-step model of myeloid leukaemogenesis, Br J Haematol, Vol: 147, Pages: 3-12, ISSN: 1365-2141

Children with Down syndrome (DS) have a marked increase in susceptibility to Acute Megakaryoblastic Leukaemia (DS-AMKL) and the closely linked neonatal preleukaemic syndrome, Transient Myeloproliferative Disorder (DS-TMD). The distinct stages of DS-TMD and DS-AMKL provide an excellent tractable model to study leukaemogenesis. This review focuses on recent studies describing clinical, haematological and biological features of DS-AMKL and DS-TMD. The findings from these studies suggest that mutations in the key haemopoietic regulator GATA1 (GATA binding protein 1) in DS-AMKL and DS-TMD may be useful in diagnosis and assessing minimal residual disease. These findings raise the possibility of population-based screening strategies for DS-TMD and the development of treatment to eliminate the preleukaemic TMD clone to prevent DS-AMKL. Advances in our understanding of perturbed haemopoiesis in DS, the role of GATA1 and of cooperating mutations are also discussed. These findings have implications for leukaemia biology more broadly given the frequency of acquired trisomy in other human leukaemias.

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Tunstall-Pedoe O, Roy A, Karadimitris A, de la Fuente J, Fisk NM, Bennett P, Norton A, Vyas P, Roberts Iet al., 2008, Abnormalities in the myeloid progenitor compartment in Down syndrome fetal liver precede acquisition of <i>GATA1</i> mutations, BLOOD, Vol: 112, Pages: 4507-4511, ISSN: 0006-4971

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• Citations: 106

De La Fuente J, O'Boyle F, Killeen N, Tso A, New H, Atra A, Dokal I, Vulliamy T, Davis J, Foroni L, Szydlo RM, Roberts Iet al., 2008, Low Dose Alemtuzumab Achieves Long-Term Engraftment with Low Level Mixed Chimerism in Related Haemopoietic Stem Cell Transplantation for Haemoglobinopathies., 50th Annual Meeting of the American-Society-of-Hematology, Publisher: AMER SOC HEMATOLOGY, Pages: 1135-1135, ISSN: 0006-4971

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Roberts I, Murray NA, 2008, Neonatal thrombocytopenia, SEMINARS IN FETAL & NEONATAL MEDICINE, Vol: 13, Pages: 256-264, ISSN: 1744-165X

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• Citations: 35

Roberts IAG, 2008, The changing face of haemolytic disease of the newborn, EARLY HUMAN DEVELOPMENT, Vol: 84, Pages: 515-523, ISSN: 0378-3782

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• Citations: 26

Roberts I, Stanworth S, Murray NA, 2008, Thrombocytopenia in the neonate, BLOOD REVIEWS, Vol: 22, Pages: 173-186, ISSN: 0268-960X

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• Citations: 112

Pinto FO, Roberts I, 2008, Cord blood stem cell transplantation for haemoglobinopathies, BRITISH JOURNAL OF HAEMATOLOGY, Vol: 141, Pages: 309-324, ISSN: 0007-1048

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• Citations: 32

Pinto FO, Roberts I, 2008, Cord blood stem cell transplantation for haemoglobinopathies, Symposium on Erythropoiesis and Red Cell Disorders, Pages: 309-324

Despite improvements in supportive care, patients with beta-thalassaemia major or sickle cell disease (SCD) may benefit from haematopoietic stem cell transplantation at some point during their lives. Human leucocyte antigen (HLA)-matched sibling bone marrow donors are not always available and alternative sources of stem cells have been sought, including related and unrelated donor cord blood transplants (CBT). The outcome of CBT from related donors for the treatment of both thalassaemia major and SCD is now approaching that for bone marrow transplantation, with around 90% of patients surviving disease-free. The main complication is graft rejection, which may be reduced by increasing pretransplant immune suppression. Transplant-related mortality following HLA-identical matched related donor CBT is extremely low but is significant in the small series of unrelated and/or mis-matched donor CBT. The principal limitation to extending the use of CB stem cells for the cure of haemoglobinopathies is the need to better understand the mechanisms of action and optimal conditioning regimens used to secure long-term engraftment while minimizing morbidity and mortality. Further biological studies and clinical trials are needed to address this aim.

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Kabbara N, Locatelli F, Rocha V, Ghavamzadeh A, Bernaudin F, Li C-K, Vermylen C, Stein J, Beruchel A, Cordonnier C, Roberts I, Socie G, Gluckman E, Walters Met al., 2008, A MULTICENTRIC COMPARATIVE ANALYSIS OF OUTCOMES OF HLA IDENTICAL RELATED CORD BLOOD AND BONE MARROW TRANSPLANTATION IN PATIENTS WITH BETA-THALASSEMIA OR SICKLE CELL DISEASE, Annual Meeting of the American-Society-for-Blood-and-Marrow-Transplantation, Publisher: ELSEVIER SCIENCE INC, Pages: 3-4, ISSN: 1083-8791

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• Citations: 6

Webb D, Roberts I, Vyas P, 2007, Haematology of down syndrome, ARCHIVES OF DISEASE IN CHILDHOOD-FETAL AND NEONATAL EDITION, Vol: 92, Pages: 503-507, ISSN: 1359-2998

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• Citations: 46

Vyas P, Norton A, Tunstall-Pedoe O, Roberts Iet al., 2007, Acute megakaryoblastic leukaemia in Down syndrome and non-Down syndrome patients - molecular signature of a disease - subtypes with distinct treatment outcomes, 14th European Cancer Conference (ECCO 14), Publisher: PERGAMON-ELSEVIER SCIENCE LTD, Pages: 36-36, ISSN: 1359-6349

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Roberts I, de Montalembert M, 2007, Sickle cell disease as a paradigm of immigration hematology: new challenges for hematologists in Europe, HAEMATOLOGICA, Vol: 92, Pages: 865-871, ISSN: 0390-6078

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• Citations: 64

Panepinto JA, Walters MC, Carreras J, Marsh J, Bredeson CN, Gale RP, Hale GA, Horan J, Hows JM, Klein JP, Pasquini R, Roberts I, Sullivan K, Eapen M, Ferster Aet al., 2007, Matched-related donor transplantation for sickle cell disease: report from the Center for International Blood and Transplant Research, BRITISH JOURNAL OF HAEMATOLOGY, Vol: 137, Pages: 479-485, ISSN: 0007-1048

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• Citations: 125

Sagoo P, Sawitzki B, Hernandez-Fuentes M, Perucha E, Craciun L, Brouard S, Chaprnan S, Bradeau C, Peters B, Roberts I, Janssen U, Soulillou JP, Warrens AN, Wood K, Goldman M, Volk HD, Lechler RIet al., 2007, Monitoring peripheral blood regulatory T cells on clinically defined groups of kidney transplant recipients., Annual American Transplant Congress, Publisher: BLACKWELL PUBLISHING, Pages: 340-340, ISSN: 1600-6135

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• Citations: 1

Almeida AM, Murakami Y, Baker A, Maeda Y, Roberts IAG, Kinoshita T, Layton DM, Karadimitris Aet al., 2007, Brief report: Targeted therapy for inherited GPI deficiency., NEW ENGLAND JOURNAL OF MEDICINE, Vol: 356, Pages: 1641-1647, ISSN: 0028-4793

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• Citations: 67

Stanworth S, Ballard S, Casbard A, Murphy M, Roberts I, Murray Net al., 2007, A multi-centre prospective observational study of platelet transfusion practice in neonates with severe thrombocytopenia, 47th Annual Scientific Meeting of the British-Society-for-Haematology, Publisher: BLACKWELL PUBLISHING, Pages: 35-36, ISSN: 0007-1048

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Murray NA, Roberts IAG, 2007, Haemolytic disease of the newborn, ARCHIVES OF DISEASE IN CHILDHOOD-FETAL AND NEONATAL EDITION, Vol: 92, Pages: F83-F88, ISSN: 1359-2998

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• Citations: 97

Murray N, Ballard S, Casbard A, Murphy M, Roberts I, Stanworth Set al., 2006, A multi-centre prospective observational study of platelet transfusion practice in neonates with severe thrombocytopenia., 48th Annual Meeting of the American-Society-of-Hematology, Publisher: AMER SOC HEMATOLOGY, Pages: 287A-287A, ISSN: 0006-4971

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• Citations: 3

Almeida AM, Murakami Y, Layton DM, Hillmen P, Sellick GS, Maeda Y, Richards S, Patterson S, Kotsianidis I, Mollica L, Crawford DH, Baker A, Ferguson M, Roberts I, Houlston R, Kinoshita T, Karadimitris Aet al., 2006, Hypomorphic promoter mutation in <i>PIGM</i> causes inherited glycosylphosphatidylinositol deficiency, NATURE MEDICINE, Vol: 12, Pages: 846-851, ISSN: 1078-8956

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• Citations: 163

Dazzi F, Ramasamy R, Glennie S, Jones SP, Roberts Iet al., 2006, The role of mesenchymal stem cells in haemopoiesis, BLOOD REVIEWS, Vol: 20, Pages: 161-171, ISSN: 0268-960X

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• Citations: 268

Kotsianidis L, Silk JD, Spanoudakis E, Patterson S, Almeida A, Schmidt RR, Tsatalas C, Bourikas G, Cerundolo V, Roberts IAG, Karadimitris Aet al., 2006, Regulation of hematopoiesis in vitro and in vivo by invariant NKT cells, BLOOD, Vol: 107, Pages: 3138-3144, ISSN: 0006-4971

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• Citations: 26

Roberts IAG, Murray NA, 2006, Neonatal thrombocytopenia., Curr Hematol Rep, Vol: 5, Pages: 55-63

Neonatal thrombocytopenia is a common clinical problem. The majority of episodes are early-onset thrombocytopenias due to impaired fetal megakaryocytopoiesis associated with placental insufficiency; the commonest causes of severe early-onset thrombocytopenia are immune thrombocytopenias, congenital infections, and asphyxia. By contrast, about 90% of cases of severe thrombocytopenia presenting after the first few days of life are due to late-onset bacterial sepsis, necrotizing enterocolitis, or both. Although clinically stable neonates tolerate relatively low platelet counts without significant risk of hemorrhage, ill or clinically unstable neonates with profound thrombocytopenia often have a poor outcome. Currently, the only therapy is platelet transfusion. Despite many published guidelines for platelet transfusion in the newborn, however, there have been no randomized trials to define the safe lower limit for platelet counts in sick neonates. The platelet threshold at which the benefits of transfusion outweigh the risks in neonates remains unclear. Well-designed trials are urgently needed.

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