This project category aims to assist potential investigators in CLL-directed research to coordinate effort for grant applications and, where possible, integrate studies between the CLLARC and other CLL dedicated groups.  At present,  It is not aimed to fund individual projects, but rather facilitate communication and develop projects that will be submitted and compete for funding through standard granting mechanisms. In the future,  it is anticipated that funding of projects may be possible.  This will be coordinated by the Leukaemia Foundation of Australia (LFA). 

The principal areas currently in this project category currently are:

• Epidemiology of CLL and Clonal Lymphocytosis of Undetermined Significance (CLUS) in Australia
• Proteomics analysis and nucleoside biology in CLL
• Immunology of BAFF and APRIL in CLL
• IGHV alignment 

i) Epidemiology of CLL and CLUS in Australia

Background:

A number of factors place Australia in a favourable position to address some of the questions regarding the epidemiology and incidence of CLL and small clones, such as:

• The distribution of the 21 million Australian population in relatively compact areas on the eastern seaboard. For example, 64% of the population is urban and up to 88.4% of the population of New South Wales is urban. There is widespread availability of high quality medical care and pathology services provided by a number of large private laboratories, including flow cytometry at a community general practice and specialist levels, as well as the public and teaching hospital system.
• Specialist haematologists, many of them affiliated with the ALLG, provide services predominantly from a relatively small number of teaching hospitals in major urban areas and account for a high proportion of the clinical care of CLL patients.
• Centralised Cancer Registries exist in each of the states of Australia with accurate statistics for CLL-related deaths. This therefore covers the spectrum of clinical presentations of CLL and related deaths, and includes the as yet poorly defined groups with “subclinical” CLL clones (Monoclonal B-Lymphcytosis [MBL] or Clonal Lymphocytosis of Undetermined Significance [CLUS]).

Since the advent of the 5-part differential haemocytometers in the early 1990s, together with flow cytometry analysis, increasingly large numbers of patients are identified with small clonal B-cell populations that were previously not detected. Rawstron et al have identified small clonal populations in 3.5% of normal individuals over 40 years and also a higher proportion (up to 13.5%) in family members of patients with CLL.^1,2 However, little data have emerged on the overall incidence of small clones in patients that present in a routine clinical setting with this incidental finding and the implications for clinical management.

Current status:

Preliminary discussions have been held between Dr Stephen Mulligan and the NSW Cancer Registry, Cancer Institute NSW  (www.cancerinstitute.org.au ) to undertake the Cancer Registry component of this study. In addition to the clinically related issues, accurate statistics of CLL in Australia that are validated by comparison with State and National Registries and quality indicators, and confirmation of data from individual laboratories by systematic analysis of their haematology and flow cytometry daily worksheet data, will provide an accurate picture of the epidemiology of CLL and related clones.   

References: 1. Rawstron AC et al. Blood 2002;100:635-9. 2. Rawstron AC et al. Blood 2002;100:2289-90.

ii) Proteomics analysis and nucleoside biology in CLL

Prof Richard Christopherson,  Molecular and Microbial Biosciences, University of Sydney.
A/Prof Stephen Mulligan, Molecular and Microbial Biosciences, University of Sydney.

Several projects related to CLL are in progress or in development at the University of Sydney.

• Continuing studies to determine the mechanism of action of cladribine and fludarabine on lymphoid cell lines, primary CLL cells and CLL cells in patients undergoing chemotherapy.
• Proteomic analysis of changes in expression of surface, cytoplasmic and nuclear proteins. 

iii) Immunology (BAFF and APRIL in CLL)

A/Prof Fabienne Mackay (Garvan Institute).

BAFF (B-cell activating factor) is a homotrimer member of the TNF superfamily, present at the cell surface or cleaved and secreted.^1,2 Another related TNF ligand, A proliferation-inducing ligand (APRIL)3 shares two receptors with BAFF, transmembrane activator and calcium-modulator and cyclophilin ligand (CAML) interactor (TACI) and B-cell maturation antigen (BCMA).^1,2 BAFF also specifically binds to a third receptor, BAFF receptor (BAFF-R, also known as BR3).^1,2 APRIL also binds to proteoglycan structures on the cell surface however, whether this interaction leads to physiological signaling is unclear.^4,5 BAFF is critical for B-cell maturation and over expression of this factor can trigger B-cell-dependent autommune disorders.^1,2 Recently, research on CLL showed that BAFF and APRIL are produced by B-CLL cells and promote the survival of these cells through an autocrine pathway.⁶ As B-CLL is thought to result from impaired apoptosis rather than proliferation, BAFF and/or APRIL may be major drivers of this disease.

1. Mackay F et al. Ann Rev Immunol 2003;21:231-264. 2. Mackay F, Browning JL. Nt Rev Immunol 2002;2:465-75. 3. Roth W et al. Cell Death Differ 2001;8:403-10. 4. Ingold K et al. J Exp Med 2005;201:1375-83. 5. Hendriks J et al. Cell Death Differ 2005;12:637-48. 6. Kern C et al. Blood 2004;103:679-88.

iv) IGHV mutation analysis

A/Prof Andrew Collins (University of New South Wales).

Chronic lymphocytic leukemia occurs in two main forms; a relatively stable form and a progressive form. The most potent prognostic indicator for the disease appears to be the level of mutation in the immunoglobulin variable genes (IGHV). This proposal plans 1. To use a novel alignment strategy to improve the cut-off of mutation numbers in IGHV genes between stable and progressive disease, 2. To evaluate the usefulness of the inclusion of immunoglobulin light chain gene mutations, 3. To evaluate mutational evidence of antigen selection in the pathogenesis of B-CLL.