Incorporating the Molly & Ted Carr Research Laboratory
Principal investigator
Staff
-
Neil Van de Water
-
Fran Porteous
- Leanne Berkahn
- Maggie Kalev
- Laura Young
Funding
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
- Van de Water, N.S., Jeeveratnam, P., Browett, P.J. et al. (1994). Direct mutational
analysis in a family with hereditary non-polyposis colorectal cancer. Aust. NZ J.
Med. 24:682-686.
- Van de Water, N.S., May, S.J., Browett, P.J. (1994). Possible misdiagnosis using
the Xba
I polymorphism for prenatal diagnosis of haemophilia A. Br. J. Haematol.
88:613-614.
- Jeeveratnam, P., Browett, P.J., Van de Water, N.S., Jass, J.R. (1995). Analysis
of Ha-ras 1 allele frequencies in hereditary non-polyposis colorectal cancer. Gut
36:382-384.
- Van de Water, N.S., Williams, R., Nelson, J., Browett, P.J. (1995). Factor VIII
inversions in severe haemophilia A patients. Pathology 27:83-85.
- Weitzer, M., Pokos, V., Jeeveratnam, P., Van de Water, N.S., Browett, P.J., Jass,
J.R. (1995). Isolated expression of the Muir-Torrew phenotype in a member of a family
with hereditary non-polyposis colorectal cancer. Histopathology 27:573-575.
- Jass, J.R., Cottie,r D.S., Jeeveratnam, P., Pokos, V., Holdaway, K.M., Bowden, M.L.,
Van de Water, N.S., Browett, P.J. (1995). Diagnostic use of microsatellite instability
in hereditary non-polyposis colorectal cancer. Lancet 346:1200-1201.
- Browett, P.J. (1996). Bone Marrow Transplantation. Patient Management 3:1-4.
- Van de Water, N.S., Williams, R., Berry, E.W., Ockelford, P.A., Browett, P.J. (1996).
Factor IX gene mutations in haemophilia B: a New Zealand population based study.
Haemophilia 2:24-27.
- Jeeveratnam, P., Cottier, D.S., Browett, P.J., Van de Water, N.S., Pokos, V., Jass,
J.R. (1996). Familial giant hyperplastic polyposis predisposing to colorectal cancer:
a new hereditary bowel cancer syndrome. J Pathol 179:20-25.
- Jass, J.R., Cottier, D.S., Jeeveratnam, P., Pokos, V., Browett, P.J. (1996). Pathology
of hereditary nonpolyposis colorectal cancer with clinical and molecular genetic
correlations. In Baba, S. Ed., New Strategies for Treatment of Hereditary Colorectal
Cancer. Churchill Livingstone, Tokyo, 29-39.
- Jass, J.R, Pokos, V., Arnold, J.L., Cottier, D.S., Jeeveratnam, P., Van de Water,
N.S., Winship, I.M., Browett, P.J. (1996). Colorectal neoplasic detected colonoscopically
in at trisk members of colorectal cancer families stratified according to the finding
of familial cancers with microsatellite instability. J Mol Med 74 (9):547-551.
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