Birmingham Chronic Lymphocytic Leukaemia (CLL) research group

Leukaemia cells

Group Leaders: Professor Paul Moss, Dr Guy Pratt, Professor Tatjana Stankovic

Overview

We are a group of scientists and doctors working together to improve the outcome for patients with chronic lymphocytic leukaemia. Our major interests are the interaction of CLL with the immune system, and how specific gene mutations in CLL influence the course of disease and may act as novel target for therapy.

Our Research Group 

The group is interested in the mechanisms that underlie the development and progression of CLL within individual patients.

At the current time there are three major areas of interest. The first is to increase knowledge of how the immune system of the patient is influenced by CLL and if this influences the ability to fight infection or respond to vaccination. In addition we investigate if the immune system plays any role in directly supporting or suppressing the growth of the tumour. A second, and related area is to study the type of tissue ‘microenvironment’ in which the tumour can develop in the lymph node. If we can understand the critical factors that support this survival then we may be able to disrupt these as a new form of treatment.

Our final area of interest relates to the type of genetic damage that accumulates in CLL tumours as they develop. We were the first group to show that mutations in the ATMgene were common in CLL and were associated with a poor response to chemotherapy. We still have a major interest in ATMbut are now investigating how the ‘evolution’ and survival of a CLL tumour cell is influenced by factors such as the choice of treatment. The aim is to help to guide the appropriate choice of treatment for each patient.

Our work is supported by kind donation of blood samples from many patients at the Queen Elizabeth Hospital and Birmingham Heartlands Hospital. 

Current Projects

We have a range of projects under investigation at the current time

  • Investigation of how CLL may affect the patient’s ability to control common chronic viral infections
  • Study of immune cells such as T and NK cells may become ‘exhausted’ in patients with CLL
  • The influence of CLL on the response to common vaccines.
  • Studying the cellular ‘architecture’ of CLL tumour cells within the lymph node and how this is supported and promoted by other cell types
  • The importance of reactive oxygen species in CLL tumours
  • Assessment of clinical importance of the ATM mutation in CLL tumours and how this may be targeted by new drug combinations.
  • Modelling of how different treatment approaches can influence the development of tumour resistance.
  • Understanding the role of CD40 Ligand, how it protects CLL cells from apoptotic signals and how it may be disrupted using novel therapies.

Recent Publications

Parry H, Birtwistle J, Whitelegg A, Hudson C, McSkeane T, Hazlewood P, Mudongo N, Pratt G, Moss P, Drayson M, Murray J, Richter A. Poor functional antibody responses are present in nearly all patients with Chronic Lymphocytic Leukaemia, irrespective of total IgG concentration, and are associated with increased risk of infection. Br J Haem 2015. Stankovic T, Skowronska A. The role of ATM mutations and 11q deletions in disease progression in chronic lymphocytic leukemia. Leuk. Lymphoma. 2014 Jun;55(6):1227-39

Rose-Zerilli MJ, Forster J, Parker H, Parker A, Rodríguez AE, Chaplin T, Gardiner A, Steele AJ, Collins A, Young BD, Skowronska A, Catovsky D, Stankovic T, Oscier DG, Strefford JC.  ATM mutation rather than BIRC3 deletion and/or mutation predicts reduced survival in 11q-deleted chronic lymphocytic leukemia: data from the UK LRF CLL4 trial. Haematologica. 2014 Apr;99(4):736-42.

Skowronska A, Parker A, Ahmed G, Oldreive C, Davis Z, Richards S, Dyer M, Matutes E, Gonzalez D, Taylor AM, Moss P, Thomas P, Oscier D, Stankovic T. Biallelic ATM inactivation significantly reduces survival in patients treated on the United Kingdom Leukemia Research Fund Chronic Lymphocytic Leukemia 4 trial. J Clin Oncol. 2012 Dec 20;30(36):4524-32.

Skowronska A, Austen B, Powell JE, Weston V, Oscier DG, Dyer MJ, Matutes E, Pratt G, Fegan C, Moss P, Taylor MA, Stankovic T. ATM germline heterozygosity does not play a role in chronic lymphocytic leukemia initiation but influences rapid disease progression through loss of the remaining ATM allele. Haematologica. 2012 Jan;97(1):142-6.

Shinawi T, Hill V, Dagklis A, Baliakas P, Stamatopoulos K, Agathanggelou A, Stankovic T, Maher ER, Ghia P, Latif F. KIBRA gene methylation is associated with unfavorable biological prognostic parameters in chronic lymphocytic leukemia. Epigenetics. 2012 Mar;7(3):211-5.

Britt-Compton B, Lin TT, Ahmed G, Weston V, Jones RE, Fegan C, Oscier DG, Stankovic T, Pepper C, Baird DM. Extreme telomere erosion in ATM-mutated and 11q-deleted CLL patients is independent of disease stage. Leukemia. 2012 Apr;26(4):826-30.

Gardiner A, Parker H, Glide S, Mould S, Robinson H, Tracy I, Stankovic T, Oscier D, Strefford J. A new minimal deleted region at 11q22.3 reveals the importance of interpretation of diminished FISH signals and the choice of probe for ATM deletion screening in chronic lymphocytic leukemia. Leuk Res. 2012 Mar;36(3):307-10.

Hayden RE, Pratt G, Roberts C, Drayson MT, Bunce CM. Treatment of chronic lymphocytic leukemia requires targeting of the protective lymph node environment with novel therapeutic approaches. Leuk Lymphoma. 2012 Apr;53(4):537-49.

Piper KP, Karanth M, McLarnon A, Kalk E, Khan N, Murray J, Pratt G, Moss PA.  Chronic lymphocytic leukaemia cells drive the global CD4+ T cell repertoire towards a regulatory phenotype and leads to the accumulation of CD4+ forkhead box P3+ T cells. Clin Exp Immunol. 2011 Nov; 166(2):154-63.

Majid A, Lin TT, Best G, Fishlock K, Hewamana S, Pratt G, Yallop D, Buggins AG, Wagner S, Kennedy BJ, Miall F, Hills R, Devereux S, Oscier DG, Dyer MJ, Fegan C, Pepper C. CD49d is an independent prognostic marker that is associated with CXCR4 expression in CLL. Leuk Res 2011 35(6); 750-6

Hayden RE, Pratt G, Drayson MT, Bunce CM (2010). Lycorine sensitizes CD40 ligand-protected chronic lymphocytic leukemia cells to bezafibbrate- and medroxyprogesterone acetate induced apoptosis but dasatinib does not overcome reported CD40-mediated drug resistance. Haematologica 2010. 95: 1889-1896

Pourgheysari B, Bruton R, Parry H, Billingham L, Fegan C, Murray J, et al. The number of cytomegalovirus-specific CD4+ T cells is markedly expanded in patients with B-cell chronic lymphocytic leukemia and determines the total CD4+ T-cell repertoire. Blood. 2010;116:2968-74.

Weston VJ, Oldreive CE, Skowronska A, Oscier DG, Pratt G, Dyer MJS, Smith G, Powell JE, Taylor AMR, Moss PAH, Stankovic T. The PARP inhibitor olaparib suppresses growth of ATM mutant lymphoid tumour cells in vitro and in vivo. Blood 2010; 116(22):4578-87

Hayden RE, Pratt G, Davies NJ, Khanim FL, Birtwistle J, Delgado J, Pearce C, Sant T, Drayson MT, Bunce CM. Treatment of primary CLL cells with bezafibrate and medroxyprogesterone acetate induces apoptosis and represses the pro-proliferative signal of CD40-ligand, in part through increased 15dDelta12,14,PGJ2. Leukemia. 2009; 23(2):292-304.

Dunwell TL, Dickinson RE, Stankovic T, Dallol A, Weston V, Austen B, Catchpoole D, Maher ER, Latif F. Frequent epigenetic inactivation of the SLIT2 gene in chronic and acute lymphocytic leukemia. Epigenetics. 2009 May;4(4):265-69. 

Gunawardana C, Austen B, Powell JE, Fegan C, Wandroo F, Jacobs A, Pratt G, Moss P. South Asian chronic lymphocytic leukaemia patients have more rapid disease progression in comparison to White patients. Br J Haematol. 2008 Aug;142(4):606-9.

Best OG, Gardiner AC, Majid A, Walewska R, Austen B, Skowronska A, Ibbotson R, Stankovic T, Dyer MJ, Oscier DG. A novel functional assay using etoposide plus nutlin-3a detects and distinguishes between ATM and TP53 mutations in CLL. Leukemia. 2008 Jul;22(7):1456-9.

Sameith K, Antczak P, Marston E, Turan N, Maier D, Stankovic T, Falciani F. (2008) Functional Modules integrating essential cellular functions are predictive of the response of leukaemia cells to DNA damage. Bioinformatics. 2008; 24:2602-7. ?

Pepper C, Lin TT, Pratt G, Hewamana S, Brennan P, Hiller L, Hills R, Ward R, Starczynski J, Austen B, Hooper L, Stankovic T, Fegan C. Mcl-1 expression has in vitro and in vivo significance in chronic lymphocytic leukemia and is associated with other poor prognostic markers. Blood 2008;112:3807-17 ??

Austen B, Skowronska A, Baker C, Powell JE, Gardiner A, Oscier D, et al. Mutation status of the residual ATM allele is an important determinant of the cellular response to chemotherapy and survival in patients with chronic lymphocytic leukemia containing an 11q deletion. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2007;25:5448-57.

Austen B, Powell JE, Alvi A, Edwards I, Hooper L, Starczynski J, Taylor AM, Fegan C, Moss P, Stankovic T. Mutations in the ATM gene lead to impaired overall and treatment-free survival that is independent of IGVH mutation status in patients with B-CLL. Blood. 2005 Nov 1;106(9):3175-82.

Alvi AJ, Austen B, Weston VJ, Fegan C, MacCallum D, Gianella-Borradori A, Lane DP, Hubank M, Powell JE, Wei W, Taylor AM, Moss PA, Stankovic T. A novel CDK inhibitor, CYC202 (R-roscovitine), overcomes the defect in p53-dependent apoptosis in B-CLL by down-regulation of genes involved in transcription regulation and survival. Blood. 2005 Jun 1;105(11):4484-91.

Stankovic T, Hubank M, Cronin D, Stewart GS, Fletcher D, Bignell CR, Alvi AJ, Austen B, Weston VJ, Fegan C, Byrd PJ, Moss PA, Taylor AM. Microarray analysis reveals that TP53- and ATM-mutant B-CLLs share a defect in activating proapoptotic responses after DNA damage but are distinguished by major differences in activating pro survival responses. Blood. 2004 Jan 1;103(1):291-300.

Stankovic T, Stewart GS, Byrd P, Fegan C, Moss PA, Taylor AM. ATM mutations in sporadic lymphoid tumours. Leuk Lymphoma. 2002 Aug;43(8):1563-71.

Stankovic T, Stewart GS, Fegan C, Biggs P, Last J, Byrd PJ, Keenan RD, Moss PA, Taylor AM. Ataxia telangiectasia mutated-deficient B-cell chronic lymphocytic leukemia occurs in pre-germinal center cells and results in defective damage response and unrepaired chromosome damage. Blood. 2002 Jan 1;99(1):300-9.

Pettitt AR, Sherrington PD, Stewart G, Cawley JC, Taylor AM, Stankovic T. p53 dysfunction in B-cell chronic lymphocytic leukemia: inactivation of ATM as an alternative to TP53 mutation. Blood. 2001 Aug 1;98(3):814-22.

Stankovic T, Weber P, Stewart G, Bedenham T, Murray J, Byrd PJ, Moss PA, Taylor AM. Inactivation of ataxia telangiectasia mutated gene in B-cell chronic lymphocytic leukaemia. Lancet. 1999 Jan 2;353(9146):26-9.

Moss PA, Gillespie G. Clonal populations of T-cells in patients with B-cell malignancies.   Leuk Lymphoma. 1997 Oct;27(3-4):231-8.

Staff

Guy Pratt is a Senior Lecturer in Haematology in the school of cancer studies and an Honorary Consultant Haematologist at The Heart of England NHS Foundation Trust. He has a specialist interest in plasma cell disorders (multiple myeloma) and CLL. He is Chief Investigator for the PICCLE trial of a PARP inhibitor in CLL, funded by the Leukaemia and Lymphoma Research body and collaborates with groups both locally and nationally.

Paul Moss is a Professor of Haematology at the University of Birmingham and Consultant Haematologist at the University Hospital NHS Foundation Trust where he leads the clinical service for CLL. His research interests are within the immune response to cancer and viruses. Clinically he leads several novel clinical trials and sits on the National Haematology Clinical Trials Studies Group.

Tatjana Stankovic is a Professor in Cancer Genetics at Birmingham University and is interested in the role of the DNA damage response in the pathogenesis of CLL. The main focus is on the loss of function of principal DNA damage response genes ATM and TP53 and how these influence disease progression and therapeutic responses.

Helen Parry is a Clinical Research Fellow at the University of Birmingham and University Hospital NHS Foundation. Her interest is in the immune response to Cytomegalovirus in CLL patients and T cell dysfunction in this disease. She is also investigating the secondary immunodeficiency in CLL and its management and the function of NK cells in CLL.

Ceri Oldrieve is a post-doctoral fellow who works on the optimisation of a model to recapitulate the heterogeneity of CLL in order to facilitate research into CLL biology and the therapeutic response to novel drugs leading to personalised treatment. Analysis of the patient ATM status of patients enrolled in the PICCLe trial, in which the tolerability and efficacy of Olaparib (a PARP inhibitor) is being assessed.

Nick Davies is a post-doctoral fellow investigating how clonal evolution in leukaemia contributes to the heterogeneity of the disease. This hetereogeneity is believed to play a critical role in how the disease progresses and its response to therapy.  Currently his research is focused on developing novel ways to track subclones within leukaemia to assess disease progression and the impact of different therapeutic modalities on clonality both in patients and a novel xenograft model.

Jane Birtwistle is a Clinical Scientist working in the Department of Immunology and has an interest in the humoral immunity of CLL patients. Her current work includes looking at functional antibody levels and vaccine responses of patients and how this correlates with their infection history.

Rachel Hayden is a post-doctoral fellow based in the School of Biosciences, currently researching the role of CD40L in the lymph node of CLL and how it may be disrupted, utilising both established and novel therapies. 

Laura Cronin is a Doctoral Researcher, investigating the microenvironment of CLL within lymph node tissue utilising fluorescent microscopy. Building up a holistic view of these tissues will allow better understanding of the disease, its establishment and progression and will open up avenues for therapeutic targeting.

Marwan Kwok is a clinical research fellow at the University of Birmingham and Queen Elizabeth Hospital Birmingham. His current projects include investigating the ATR pathway as a novel therapeutic target for relapsed/refractory CLL and determining the clinical impact of small subclonal ATM mutations by ultra-deep ATM sequencing. He is also interested in understanding the mechanism underlying genomic instability and therapeutic resistance in relapsed/refractory CLL patients.

The image above is a x10 objective tile scan image of a section of CLL LN which has a distinct area of proliferation within frame. This image was taken on a Zeiss Zen780 (IBR MISBU facility, University of Birmingham). Key; CD3 = green, Ki-67 = blue, Pax5 = red (purple = proliferating B cells).  A larger version of the image can be viewed by clicking on it.