Principal Investigator: Professor Nicolas Novitzky
Glenda Davison. PhD Student
In myelodysplastic syndromes (MDS) disregulation of the immune system seems to result in increased apoptosis of bone marrow cells with consequent pancytopenia and in some patients, clinical autoimmune phenomena. Wether T-cells form part of the malignant clone remains debatable as these are long lived memory cells. Glenda Davison is looking at clonality and function of the T-cell population and their interaction with dendritic cells in MDS for her PhD thesis.
Principal Investigator: Dr Karen Shires
1) The search for a CML-specific antigen: An investigation into the changes that occur at the cell surface as a result of transformation with active BCR-ABL.
In the era of targeted drug therapy, being able to uniquely identify and destroy malignant cells is critical to successful treatment. Chronic myelogenous leukemia is a haematopoietic malignancy characterised by a specific genetic mutation, the bcr-abl fusion gene. BCR-ABL expression is unique to the malignant clone and plays a direct role in disease pathogenesis. We plan to identify cell surface antigens that are unique to cells expressing BCR-ABL (CML-specific antigens), through phage display analysis (peptide library) and two-dimensional protein analysis of bcr-abl transformed human fibroblasts
2) Bone marrow transplant stromal damage: identification of the damaged signaling pathways involved in stem cell homing and self renewal.
Bone marrow stromal damage caused by pre-BMT myeloablative therapy (chemotherapy/radiation) has been implicated as a cause of the reduced long-term hematopoietic potential observed in transplant patients. In order to improve patient prognosis it is imperative to define the stromal/HSC signaling pathways that are affected by this therapy. We will assess radiation-induced stromal damage by microarray analysis, concentrating on expression of genes specifically involved in HSC homing and self renewal. The altered expression of selected genes will then be analysed in BMT stromal cultures and the functioning of the affected pathways investigated, to confirm the in vivo damage to these pathways
3) Cancer/Testis antigen expression in Multiple Myeloma
Cancer/Testis antigens (CTAs) are a group of highly immunogenic proteins that show testis-restricted expression in normal tissue, but high expression in many different cancer types. In recent years CTA expression in Multiple Myeloma (MM) has been explored, with the discovery that some of these antigens are commonly expressed. Their expression has been linked with advanced disease and poor overall survival. Although they are being actively investigated for immunotherapy uses, little is known about their role in MM pathogenesis. In an attempt to understand both their role in disease and as a potential prognostic tool, we plan to investigate the expression of a panel of commonly expressed CTAs in MM and associate this with more classical MM prognostic factors.
4) Unraveling apoptosis malfunctions in Myelodysplastic syndromes
Apoptosis has been implicated as having a key role in the pathogenesis of MDS, yet the exact mechanisms (apoptosis pathways and specific cell types) responsible for the observed apoptotic increase are poorly defined. We plan to use fractionated, homogeneous cell populations (i.e: CD34+ progenitors sub-populations, fibroblasts, macrophages) from MDS patients in a novel study where aspects of the three different apoptotic pathways: death-receptor, mitochondrial and ER-stress-induced are simultaneously investigated, to give a comprehensive indication of the extent of apoptosis malfunction in MDS.
Principal Investigator: Dr Shaheen Mowla
Burkitt's lymphoma (BL), a highly aggressive cancer, is the most common malignancy among HIV positive patients in South Africa. While the use of highly active antiretroviral therapy significantly improves the survival of patients with other forms of HIV-related lymphomas, the cancer continues to progress unabated. Therefore, the risk of HIV-associated BL appears to be independent of CD4 count / immuno-status, and suggests a more direct and active role by the virus. While it was previously generally assumed that HIV infection has only an indirect role in the development of cancer through impairment of the immune system, recent evidence suggests a more direct role through viral encoded proteins. The hallmark of all BL cases is the upregulation of the c-MYC transcription factor due to chromosomal translocations placing the c-MYC gene under the regulation of the highly active immunoglobulin gene locus in B lymphocytes. My research interest is to investigate the impact and contribution of HIV infection on the molecular mechanisms regulating c-MYC translocation, regulation and downstream targets in Burkitt's lymphoma development and pathogenesis.
MicroRNAs (miRNA) are small, highly conserved noncoding RNA molecules and are thought to regulate up to 30% of human protein coding genes. The discovery in the last decade that these small molecules are specific regulators of gene expression is novel and an exciting breakthrough in the Biological Sciences. MicroRNAs regulate their target genes either by degrading messenger RNA through the RNA interference pathway or by inhibiting protein translation. The biological roles of most mammalian miRNAs are still poorly understood, but studies in invertebrates have shown that they regulate developmental timing, organ differentiation, cell proliferation and apoptosis. Since development of cancer is ultimately a consequence of disordered gene expression, miRNAs have been suggested to play a significant role in carcinogenesis. This is supported by the observation that the earliest miRNAs discovered in invertebrates were shown to control cell proliferation and apoptosis, and their deregulation may therefore contribute to proliferative diseases such as cancer. Additionally, many miRNA genes in humans are located at genomic sites which are commonly amplified or deleted in cancers and comparative studies have shown widespread deregulation of miRNA expressions in cancer compared to normal cells. While the role of miRNAs in human haematopoiesis has been extensively studied, their expressions and roles in haematological malignancies remain mostly unexplored. It is estimated that 3% of human genes encode miRNAs, however only two, miR-155 and miR-17-92, have been demonstrated to have clear oncogenic roles in human haematologic cancers. Several others have been found to be deregulated, however, their exact roles still need to be elucidated. My research focuses on identifying differentially expressed miRNAs in Burkitt's lymphoma cells (from both AIDS-related as well as non-immuno-compromised BL patients) in comparison with normal lymphoid cells and to characterize their roles in the development of the disease.
Principal Investigator: Dr Jessica Opie
Coagulation abnormalities particularly thrombophilias
HIV in Haematology: Bone marrow changes and peripheral blood cytopenias