Tumour B-cells From Lymphomas Are Resistant To ATP-mediated Apoptosis Due To Non-functional P2X7 Receptors
Funder
National Health and Medical Research Council
Funding Amount
$226,320.00
Summary
Adenosine triphosphate (ATP) is an important constituent normally present inside cells. When added to normal lymphocytes (or released by cells lining the vessel wall or in lymph nodes), ATP acts from outside these cells to open a pore as well as activate an enzyme which digests the lipid envelope of the cell. This loss of lipid covering of the cell produces a leakiness to various constituents of the cell which gradually leads to death of normal lymphocytes. However in the malignant lymphocytes o ....Adenosine triphosphate (ATP) is an important constituent normally present inside cells. When added to normal lymphocytes (or released by cells lining the vessel wall or in lymph nodes), ATP acts from outside these cells to open a pore as well as activate an enzyme which digests the lipid envelope of the cell. This loss of lipid covering of the cell produces a leakiness to various constituents of the cell which gradually leads to death of normal lymphocytes. However in the malignant lymphocytes of human lymphomas this mechanism of cell death does not operate. The loss of function of this 'death receptor' explains why in the lymphomas there is a progressive accumulation of malignant lymphocytes which give enlargement of lymph nodes and spleen and leads to death of the patient. Knowledge of the defect in this pathway of cell death will enable new strategies to be introduced to control this malignant disease.Read moreRead less
Microenvironmental Regulation Of Blood Cells By Retinoic Acid Receptor Gamma.
Funder
National Health and Medical Research Council
Funding Amount
$958,428.00
Summary
Vitamin A deficiency causes profound effects in humans, with anaemia and an inability to fight infection being consequences of vitamin A deficiency on blood cells. We have evidence that these effects of vitamin A deficiency occur via one of the receptors for vitamin A. Furthermore, these effects are due to changes in the non-blood cells that help to make blood cells. By understanding how this occurs we may identify better treatments for patients with impaired immune systems.
CXCR4 Antagonists In Acute Lymphoblastic Leukemias In NOD/SCID Mice
Funder
National Health and Medical Research Council
Funding Amount
$505,500.00
Summary
Acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer and a major cause of death in children. Although ALL is usually responsive to chemotherapy, about 25% of children and 65% of adults with ALL develop a relapse of their disease. The majority of these patients will die of leukemia. New approaches to the treatment of ALL are necessary to obtain cures for these patients. We have identified stromal-derived factor (SDF)-1 as a major regulator of ALL cell growth and survival ....Acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer and a major cause of death in children. Although ALL is usually responsive to chemotherapy, about 25% of children and 65% of adults with ALL develop a relapse of their disease. The majority of these patients will die of leukemia. New approaches to the treatment of ALL are necessary to obtain cures for these patients. We have identified stromal-derived factor (SDF)-1 as a major regulator of ALL cell growth and survival. It is currently the only known factor that significantly stimulates the growth-survival of cells from the majority of patients with ALL. Specific antagonists of the SDF-1 receptor, CXCR4, are available. Depriving ALL cells of SDF-1 by the use of these antagonists provides a radically new approach for the treatment of ALL. CXCR4 antagonists also increase the susceptibility of ALL cells to cytotoxic drugs. The mechanisms by which SDF-1 promotes ALL cell growth and survival are not known but appear to be largely due to synergistic interactions with other molecules that have little or no effect on their own. Knowledge of the underlying mechanisms of action of SDF-1 and the factors with which it synergises will facilitate for the further development of this approach. This project will examine the modulation of the expression of proteins that regulate ALL cell growth and survival by CXCR4 antagonists, providing insights into how CXCR4 antagonists work. This project will also extend our encouraging data obtained using tissue culture to an animal model of leukemia. The antagonists will be tested in isolation and in combination with currently used chemotherapy agents. It is expected that CXCR4 antagonists will inhibit the growth of ALL cells and increase their sensitivity to chemotherapy agents in the animal model as we have seen in laboratory culture. The addition of CXCR4 antagonists to current treatment protocols is expected to significantly improve the outcome for patients.Read moreRead less
Antagonists Of P38 MAPK As Therapeutics For Acute Lymphoblastic Leukemia.
Funder
National Health and Medical Research Council
Funding Amount
$521,961.00
Summary
New therapies are needed to treat patients with leukemia. Moving leukemic cells into the blood reduces their growth and increases the effects of chemotherapy. Currently we cannot move leukemic cells into the blood without moving normal blood forming cells, making them more sensitive to chemotherapy. We have identified a drug that only affects leukemic cell movement. This study will examine the potential of this drug to treat leukemia.
The Role Of Ap2a2 In Self-renewal Of Haematopoietic And Leukemic Stem Cells
Funder
National Health and Medical Research Council
Funding Amount
$579,171.00
Summary
The daily replenishment of the blood system is dependent on the blood stem cell. A unique property of these stem cells is self-renewal where the stem cell function is preserved, whilst other daughter cells continue to divide. Our research investigates the molecular mechanisms that regulate stem cell self-renewal. This work has potential clinical application on at least two levels: expansion of stem cells for transplantation, and for attacking abnormal cancer cell self-renewal pathways.
Role Of The Hypoxia-inducible Transcription Factor HIF-1a In Controlling Haematopoietic Stem Cell Fate
Funder
National Health and Medical Research Council
Funding Amount
$586,428.00
Summary
Haematopoietic stem cells (HSCs) reside in the bone marrow (BM) and make all immune and blood cells. We have found that, in the areas of the BM where HSC normally live, the level of oxygen is very low (hypoxia) and decreases even further when HSC are forced to move into the blood in order to be collected for transplantation. This project is to better understand how oxygenation of the BM controls HSC behaviour and properties, and to evaluate its impact on HSC transplantation.