School of Medical Sciences


Molecular haematology and laboratory medicine

Incorporating the Molly & Ted Carr Research Laboratory

Principal investigator


Staff


  • Neil Van de Water
  • Fran Porteous
  • Leanne Berkahn
  • Maggie Kalev
  • Laura Young

Research


The haematology research group is a collaboration between The University of Auckland and the Clinical and Laboratory Haematology Services, Auckland District Health Board. This has resulted in the establishment of the Mollie and Ted Carr Research Laboratory as part of the development of an active bone marrow transplant research and treatment facility in Auckland. The Mollie and Ted Carr Laboratory will focus on new strategies for purifying haematopoietic stem cells for clinical use as well as fostering the ongoing research programmes in Haematology, including studies on the genetics of haemophilia and prothrombotic disorders, mutation analysis in familial cancer syndromes, and assessment of minimal residual disease in patients with leukaemia and other cancers.

Research areas


Bone marrow transplantation

Immunomagnetic selection of haematopoietic stem cells Autologous bone marrow and peripheral blood progenitor transplantation is an important part of the modern therapy of patients with leukaemia and other malignancies, however gene marker studies suggest contaminating leukaemia cells in the autograft may contribute to recurrence of the leukaemia. The aim of these studies is to purify haematopoietic stem cell populations using immunomagnetic bead and FACS cell sorting technology. These cell populations will be analyzed for purity, tumour contamination and repopulating potential, before proceeding to clinical studies of CD34 selected haematopoietic stem cells in the transplant setting.

Mini-allograft procedures

The group is about to initiate a trial evaluating the role of mini-allografts in the treatment of patients with low grade haematological malignancies eg. non-HodgkinÕs lymphoma, myeloma, CLL, CML. Patients receive less intensive conditioning therapy prior to the infusion of stem cells, utilizing the "graft versus leukaemia" effect from the donor immune system to control and eradicate residual tumour cells. Laboratory components of the study will include assessment of chimaerism in T cell and myeloid cells post transplant, as well as monitoring for minimal residual disease.

BMT ClinicBMT clinical studies

The group is also co-ordinating Auckland participation in several multicentre and local transplant studies. These are as follows: High dose therapy and autologous stem cell transplantation versus conventional chemotherapy for poor prognosis HodgkinÕs disease. Early high dose therapy and autologous stem cell transplantation versus conventional chemotherapy for patients with intermediate grade non-HodgkinÕs lymphoma with poor prognostic features.

Early autologous stem cell transplantation in adult acute lymphoblastic leukaemia.

Outpatient autologous stem cell transplantation for non-leukaemic malignancies.

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Molecular genetics: characterisation of inherited coagulation and thrombotic disorders

Haemophilia studies

The laboratory is responsible for providing prenatal and carrier diagnostic services for families with haemophilia and thalassaemia. This role is supported by an active research programme, primarily looking at mutations within the factor VIII and factor IX genes which may cause haemophilia. This data is correlated with the clinical phenotype, as well as facilitating direct mutational analysis for families with haemophilia.

Prothrombotic disorders

It has recently been recognised that resistance to the antithrombotic effects of protein C (activated protein C resistance) is a major genetic risk factor for venous thrombosis. In most cases APC resistance is due to a point mutation in the factor V gene which makes the coagulation factor resistant to cleavage by protein C. We, and others, have demonstrated the incidence of heterozygosity for this mutation to be approximately 4% in the general population but up to 30% of patients with venous thrombo-embolic disease carry the mutation. The role of APC resistance/factor V Leiden mutation in arterial disease is less clear, and the objective of this study is to examine the prevalence of this mutation and other genetic risk factors in patients with myocardial infarction who have minimal evidence of atherosclerosis on coronary angiography.

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Leukaemia Studies: minimal residual disease detection

The major focus of these studies is to develop and evaluate molecular and immunophenotypic strategies for the early detection of relapse in leukaemic patients treated with either chemotherapy or stem cell transplantation. Strategies currently being studied include: Quantitative PCR (real time PCR) monitoring of leukaemic translocations. Monitoring of aberrant immunophenotype in paediatric and adult ALL.

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Familial cancer syndromes (in collaboration with A/Prof Ingrid Winship)

Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

It is now clear that in 5-10% of cases of the common malignancies there is a familial component. Germline mutations within members of a family of DNA mismatch repair genes, resulting in genomic instability, have recently been implicated in the pathogenesis of HNPCC. We have identified a point mutation within one of the mismatch repair genes, hMSH2, which has allowed development of a rapid PCR based screening assay for the mutation. Current objectives of this study include: Mutation analysis of the DNA mismatch repair genes in families with HNPCC.

"Second hit" analysis in the tumours of subjects from HNPCC families.

Analysis of microsatellite instability as a marker of HNPCC.

Searching for new genes which may be implicated in familial colorectal cancer in families which fulfil criteria for HNPCC but do not show microsatellite instability and do not have evidence of mutations within the known DNA mismatch repair genes. Evaluation of microsatellite instability in young patients with colorectal cancer.

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Clinical studies

Members of the group are actively involved in the design and co-ordination of a number of clinical studies in the fields of haematology and oncology. Current studies include: Empiric therapy of neutropenic fever in patients with haematological malignancies (principle investigator, multicentre study). Transplant studies (multicentre, listed in BMT research section). Lymphoma studies: Super CEOP plus growth factor support versus standard dose CEOP in patients intermediate grade NHL (principal investigator for New Zealand, ANZ Lymphoma Group Study). High dose therapy with stem cell support for patients with advanced stage breast cancer (collaboration with Oncology Service).

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Recent relevant publications


  1. Linch D.C., Yung L., Smith P., Maclennan K., Jack A., Hancock B., Cunningham D., Hoskin P., Qian W., Holte H., Boesen A.M., Grigg A., Browett P., Trneny M. (2010).  Final analysis of the UKLG LY02 trial comparing 6-8 cycles of CHOP with 3 cycles of CHOP followed by a BEAM autograft in patients <65 years with poor prognosis histologically aggressive NHL. Br. J. Haematol 149(2):237-4.
  2. Dare T., Findlay M., Browett P., Amies K., Anderson S. (2010). Paternalism in practice: informing patients about expensive unsubsidised drugs. J Med. Ethics 36(5):260-4.
  3. O'Sullivan S., Naot D., Callon K.E., Watson M., Gamble G.D., Ladefoged M., Karsdal M.A., Browett P., Cornish J., Grey A. (2011).  Imatinib mesylate does not increase bone volume in vivo. Calcif. Tissue Int. 88(1):16-22.
  4. O'Sullivan S., Lin J.M. Watson M., Callon K., Tong P.C., Naot D., Horne A., Aati O., Porteous F., Gamble G., Cornish J., Browett P., Grey A. (2011). The skeletal effects of the tyrosine kinase inhibitor nilotinib.  Bone 49(2):281-9.
  5. Jüllig M., Browett P., Middleditch M.M., Prijic G., Kilfoyle D., Angelo N., Cooper G.J. (2011). A unique case of neural amyloidoma diagnosed by mass spectrometry of formalin-fixed tissue using a novel preparative technique. Amyloid 18(3):147-55.
  6. Iland H.J., Bradstock K., Seymour J., Hertzberg M., Grigg A., Taylor K., Catalano J., Cannell P., Horvath N., Deveridge S., Browett P., Brighton T., Li C., Springall F., Ayling J., Catalano A., Supple S., Collins M., Di Iulio J., Reynolds J. (2012). Results of the APML3 trial incorporating all-trans-retinoic acid and idarubicin in both induction and consolidation as initial therapy for patients with acute promyelocytic leukemia. Haematologica 97(2): 227-34.
  7. Iland H.J., Bradstock K., Supple S.G., Catalano A., Collins M., Hertzberg M., Browett P., Grigg A., Firkin F., Hugman A., Reynolds J., Di Iulio J., Tiley C., Taylor K, Filshie R., Seldon M., Taper J., Szer J., Moore J., Bashford J., Seymour J.F.; Australasian Leukaemia and Lymphoma Group. (2012). All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood 120(8):1570-802.
  8. Young L.K., Birch N.P., Browett P.J., Coughlin P.B., Horvath A.J., Van de Water N.S., Ockelford P.A., Harper P.L. (2012). Two missense mutations identified in venous thrombosis patients impair the inhibitory function of the protein Z dependent protease inhibitor. Thromb. Haemost. 107(5):854-63.
  9. Campbell L.J., Oei P., Brookwell R., Shortt J., Eaddy N., Ng A., Chew E., Browett P.J. (2013). FISH detection of PML-RARA fusion in ins(15;17) acute promyelocytic leukaemia depends on probe size. Biomed. Res. Int.;2013:1645013.
  10. Koopmans W., Woon S.T., Zeng I.S., Jordan A., Brothers S., Browett P., Ameratunga R. (2013). Variability of memory B cell markers in a cohort of common variable immune deficiency patients over 6 months.  Scand. J. Immunol. 77(6):470-5.
  11. O'Sullivan S., Horne A., Wattie D., Porteous F., Gamble G., Browett P., Grey A. (2013). Bone metabolism during long term treatment with imatinib.  Leuk. Lymphoma. Jan 24. [Epub ahead of print] .
  12. Koopmans W., Woon S.T., Brooks A.E., Dunbar P.R., Browett P., Ameratunga R. (2013). Clinical variability of family members with the C104R mutation in transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI). J. Clin. Immunol. 33(1):68-73.
  13. Experts in Chronic Myeloid Leukemia. (2013). The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: from the perspective of a large group of CML experts.  Blood. May 30;121(22):4439-42. doi: 10.1182/blood-2013-03-490003. Epub 2013 Apr 25.
  14. Mant S., Taylor G., Dutton D., Butler A., Browett P., Ganly P. (2014). Development of T-cell lymphomas with an activated cytotoxic immunophenotype, including anaplastic large cell lymphomas, in patients with chronic lymphocytic leukaemia: a series of six cases. Leuk. Lymphoma. May 31:1-9. [Epub ahead of print] No abstract available.
  15. Burns K.E., Goldthorpe M.A., Porteous F., Browett P., Helsby N.A. (2014). CYP2C19 genotype-phenotype discordance in patients with multiple myeloma leads to an acquired loss of drug-metabolising activity. Cancer Chemother. Pharmacol. Mar;73(3):651-5. doi: 10.1007/s00280-014-2409-9. Epub 2014 Feb 12.
  16. Li X.Q., Cheuk W., Lam P.W., Wang Z., Loong F., Yeong M.L., Browett P., McCall J., Chan J.K. (2014).  Inflammatory pseudotumor-like follicular dendritic cell tumor of liver and spleen: granulomatous and eosinophil-rich variants mimicking inflammatory or infective lesions. Am. J. Surg. Pathol. May;38(5):646-53. doi: 10.1097/PAS.0000000000000170.
  17. Hertzberg M., Matthews J.P., Stone J.M., Dubosq M.C., Grigg A., Ellis D., Benson W., Browett P., Horvath N., Januszewicz H., Abdi E., Green M., Bonaventura A., Marlton P.Cannell P., Wolf M; ALLG (2014). A phase III randomized trial of high-dose CEOP + filgrastim versus standard-dose CEOP in patients with non-Hodgkin lymphoma: 10-year follow-up data: Australasian Leukaemia and Lymphoma Group (ALLG) NHL07 trial. Am. J. Hematol.  May;89(5):536-41. doi: 10.1002/ajh.23684. Epub 2014 Feb 21.

 

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