Eradicating Leukaemic Stem Cells By Targeting The Arginine Methyltransferase PRMT5
Funder
National Health and Medical Research Council
Funding Amount
$770,950.00
Summary
Acute leukemia is a devastating cancer arising from primitive cells in the bone marrow called stem cells. We have identified a protein (PRMT5) that is highly expressed in leukemia stem cells. Our preliminary experiments suggest that blocking the function of this protein with a novel drug can stop the growth of these cells. This project will use a variety of mouse models of acute leukemia to determine how PRMT5 keeps stem cells alive and whether this drug will be a valuable new treatment.
We want to understand more about the control of blood cell formation and the development of leukemia. We have discovered one gene that is very important in both these processes. It is the most common genetic abnormality involved in causing human T-cell leukemia, and we have recently shown that it is absolutely required for the development of all blood cells within an animal. We wish to take these observations further so that we can ultimately understand how a gene important in blood cell formati ....We want to understand more about the control of blood cell formation and the development of leukemia. We have discovered one gene that is very important in both these processes. It is the most common genetic abnormality involved in causing human T-cell leukemia, and we have recently shown that it is absolutely required for the development of all blood cells within an animal. We wish to take these observations further so that we can ultimately understand how a gene important in blood cell formation can also be important in causing leukemia. Here we propose to use genetic engineering approaches to generate mice in which the function of this gene is ablated or removed in a controlled and regulated fashion.Read moreRead less
Analysis Of The Hematopoietic Function Of Endophilin And MASH Proteins
Funder
National Health and Medical Research Council
Funding Amount
$408,055.00
Summary
We want to understand more about the control of blood cell formation and the development of leukaemia. We have discovered one gene that is very important in both these processes. It is the most common genetic abnormality involved in causing human T-cell leukaemia and we have recently shown that it is absolutely required for the development of all blood cells within an animal. We wish to understand how a gene important in blood cell formation can also be important in causing leukaemia. To address ....We want to understand more about the control of blood cell formation and the development of leukaemia. We have discovered one gene that is very important in both these processes. It is the most common genetic abnormality involved in causing human T-cell leukaemia and we have recently shown that it is absolutely required for the development of all blood cells within an animal. We wish to understand how a gene important in blood cell formation can also be important in causing leukaemia. To address this we will study a new molecule with which it partners, and two molecules via which it exerts its actions.Read moreRead less
We want to understand more about the control of blood cell formation and the development of leukaemia. We have discovered one gene that is very important in both these processes. It is the most common genetic abnormality involved in causing human T-cell leukaemia and we have recently shown that it is absolutely required for the development of all blood cells within an animal. We wish to take these observations further so that we can ultimately understand how a gene important in blood cell format ....We want to understand more about the control of blood cell formation and the development of leukaemia. We have discovered one gene that is very important in both these processes. It is the most common genetic abnormality involved in causing human T-cell leukaemia and we have recently shown that it is absolutely required for the development of all blood cells within an animal. We wish to take these observations further so that we can ultimately understand how a gene important in blood cell formation can also be important in causing leukaemia. To address this we will generate new models of blood cell development.Read moreRead less
The Roles Of Retinoids And Their Receptors In Haemopoiesis
Funder
National Health and Medical Research Council
Funding Amount
$474,750.00
Summary
Haemopoietic stem cells (HSCs) are the most widely studied adult somatic stem cell. HSCs have huge potential, sustaining blood cell production throughout an individual's life. Cancers (leukaemias) and other disorders of the blood are largely treated by transplantation of HSCs. However, due to their rare occurrence, it is often difficult to obtain large numbers of HSCs for transplantation, especially from sources of HSCs such as cord blood. Furthermore, protocols requiring manipulation of HSCs, s ....Haemopoietic stem cells (HSCs) are the most widely studied adult somatic stem cell. HSCs have huge potential, sustaining blood cell production throughout an individual's life. Cancers (leukaemias) and other disorders of the blood are largely treated by transplantation of HSCs. However, due to their rare occurrence, it is often difficult to obtain large numbers of HSCs for transplantation, especially from sources of HSCs such as cord blood. Furthermore, protocols requiring manipulation of HSCs, such as gene therapy, have been largely unsuccessful, in part due to the lack of success in growing HSCs outside of the body. In such situations, therefore, determining culture conditions that would enable us to grow HSCs outside of the body are highly desirable. This application is based on the studies of CIA, who recently made the novel discoveries that the vitamin A derivative, all-trans retinoic acid (ATRA) has different effects in the regulation of blood cell production. ATRA is currently used in the treatment of acute promyelocytic leukaemia, as it enhances the maturation of the leukaemic cells. CIA has demonstrated that ATRA has the opposite effect on HSCs, with recent data strongly suggesting that ATRA induces the expansion of HSCs outside of the body. The studies outlined in this proposal seek to further define the mechanisms involved in these effects of ATRA and other vitamin A derivatives (collectively termed retinoids) in the regulation of blood cell production. The first specific aim will determine how retinoids expand HSCs. The second specific aim will explore the roles of the different RARs in the regulation of blood cell production. These studies have direct clinical relevance in improving protocols for transplantation and gene therapy of HSCs. Furthermore, insight gained into the roles of retinoids in blood cell production may also lead to the improvement of treatments of various types of blood disorders.Read moreRead less
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