Genetic Analysis Of Drug Resistance In Childhood Acute Lymphoblastic Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
Treatment for childhood leukaemia fails in approximately 25% of children owing to resistance to the drugs being used. Our recent evidence suggests that only a few rare leukaemic cells are initially resistant at the commencement of treatment. This project aims to isolate these rare cells and to look for genetic changes in them which might account for their resistance. Hopefully an understanding of the genetic basis for drug resistance will lead to better means of overcoming it.
Characterisation Of Erythropoietic Mutants Identified In A Forward Genetic Screen In Mice.
Funder
National Health and Medical Research Council
Funding Amount
$501,902.00
Summary
The human bone marrow is the pivotal organ in the replacement of the vast numbers of blood cells normally consumed each day. One of the cells regenerated by this organ are the red blood cells which are critical for the transport of oxygen to the tissues. This proposal uses genetically altered mice to identify genes that are critical for the production of normal red blood cells. Mice exposed to a chemical that induces random mutations in their genome are bred and pups with abnormal red blood cell ....The human bone marrow is the pivotal organ in the replacement of the vast numbers of blood cells normally consumed each day. One of the cells regenerated by this organ are the red blood cells which are critical for the transport of oxygen to the tissues. This proposal uses genetically altered mice to identify genes that are critical for the production of normal red blood cells. Mice exposed to a chemical that induces random mutations in their genome are bred and pups with abnormal red blood cells are identified. The responsible genetic mutation is identified and the gene is then studied to determine how it influences red blood cell production. The results of these studies provide insights into a variety of human conditions including anemia, thalassemia and sickle cell disease.Read moreRead less
Determining The Transcriptional Programme Of A Leukaemogenic Transcription Factor In Normal And Leukaemic Cells
Funder
National Health and Medical Research Council
Funding Amount
$643,958.00
Summary
Leukaemic (blood cancer) cells develop from immature blood cells by inappropriate expression of genes. These genes are also those that are required for normal blood production in the embryo. Gene expression during normal blood development is tightly controlled. However in leukaemia, these genes are expressed at inappropriate stages of blood development. We will investigate whether leukaemic cells adopt features of embryonic blood stem cells to express genes that convert normal cells into abnorma ....Leukaemic (blood cancer) cells develop from immature blood cells by inappropriate expression of genes. These genes are also those that are required for normal blood production in the embryo. Gene expression during normal blood development is tightly controlled. However in leukaemia, these genes are expressed at inappropriate stages of blood development. We will investigate whether leukaemic cells adopt features of embryonic blood stem cells to express genes that convert normal cells into abnormal cells.Read moreRead less
Identification Of The Molecular Genetic Basis Of The Hepatic Veno-occlusive Disease With Immunodeficiency Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$224,250.00
Summary
One of the most serious complications of bone marrow transplantation is veno-occlusive disease (VOD), also termed sinusoidal obstruction syndrome (SOS). This condition occurs in 10% of transplanted patients and is characterised by abnormalities of liver function, enlargement of the liver, clotting abnormalities, fluid retention and finally failure of multiple organs and death in 30-50% of cases. The cause of VOD is unknown, and its occurrence cannot be predicted in individual patients. Eight fam ....One of the most serious complications of bone marrow transplantation is veno-occlusive disease (VOD), also termed sinusoidal obstruction syndrome (SOS). This condition occurs in 10% of transplanted patients and is characterised by abnormalities of liver function, enlargement of the liver, clotting abnormalities, fluid retention and finally failure of multiple organs and death in 30-50% of cases. The cause of VOD is unknown, and its occurrence cannot be predicted in individual patients. Eight families have been described in whom a number of individuals have succumbed to a condition which is clinically and histologically indistinguishable from VOD. Affected individuals also have a form of immunodeficiency (hence termed VODI), and the abnormalities are inherited in an autosomal recessive pattern. All eight are of Lebanese origin, suggesting that a single genetic ancestral mutation was responsible for the disorder in all families, who are distantly related. We have access to genetic material from three of these families, and are on the way to identifying the causative genetic abnormality. We hypothesise that understanding this abnormality will lead to an understanding of VOD which occurs after bone marrow transplantation. We have used 800 polymorphic genetic markers scattered throughout the genome to identify the location of the genetic abnormality, and have localised the defect to a region of chromosome 2 which contains approximately 37 known and predicted genes. We now aim to determine which of the gene(s) in the candidate region is responsible for VODI, and plan to examine DNA from individuals who have had VOD after transplantation to determine if they have a related abnormality. Finding the VODI gene will benefit these families through the availability of carrier detection and may also lead to an understanding of the veno-occlusive disease that occurs after bone marrow transplantation.Read moreRead less
Inducible Caspase 9 Suicide Gene To Improve The Safety Of Donor T Cell Addback After Haploidentical Stem Cell Transplantation
Funder
National Health and Medical Research Council
Funding Amount
$566,232.00
Summary
In bone marrow transplantation, donor immune cells are important for fighting cancer cells and infections but can also attack healthy tissues, causing graft-versus-host disease (GVHD). We will use gene technology to insert a safety switch called inducible capase 9 (iCasp9) into the donor immune cells which will make them susceptible to an otherwise non-toxic chemical. This will make it safer to boost the recipients’ immunity because these cells can be rapidly eliminated if GVHD occurs.
Cell Therapy To Prevent And Treat Graft-versus-host Disease After Allogeneic Haematopoietic Stem Cell Transplantation
Funder
National Health and Medical Research Council
Funding Amount
$260,302.00
Summary
In bone marrow transplantation, donor immunity can fight the cancer but can also attack healthy tissues, causing graft-versus-host disease (GVHD). We will use two types of cell therapy to treat GVHD. The first study will use a safety switch called inducible capase 9 (iCasp9) to enable the donor immune cells to be rapidly eliminated if GVHD occurs. The second study will use regulatory T cells to treat patients with chronic GVHD. If successful, these treatment approaches will make transplantation ....In bone marrow transplantation, donor immunity can fight the cancer but can also attack healthy tissues, causing graft-versus-host disease (GVHD). We will use two types of cell therapy to treat GVHD. The first study will use a safety switch called inducible capase 9 (iCasp9) to enable the donor immune cells to be rapidly eliminated if GVHD occurs. The second study will use regulatory T cells to treat patients with chronic GVHD. If successful, these treatment approaches will make transplantation safer.Read moreRead less
The Molecular And Cellular Mechanisms Responsible For The Skeletal Complications Associated With Multiple Myeloma.
Funder
National Health and Medical Research Council
Funding Amount
$212,036.00
Summary
Multiple myeloma is an incurable disease of the antibody-producing B cell. Patients with MM, nearly always present with bone pain and unexplained bone fractures. These fractures are caused by the cancerous MM B cells, which are found in large numbers in discrete pockets throughout the bone marrow, close to the inner bone surface. The way that the cancerous B cells cause the local bone lesions is thought to be through the heightened activation of recruitment of osteoclasts. Osteoclasts are cells ....Multiple myeloma is an incurable disease of the antibody-producing B cell. Patients with MM, nearly always present with bone pain and unexplained bone fractures. These fractures are caused by the cancerous MM B cells, which are found in large numbers in discrete pockets throughout the bone marrow, close to the inner bone surface. The way that the cancerous B cells cause the local bone lesions is thought to be through the heightened activation of recruitment of osteoclasts. Osteoclasts are cells which normally, in a controlled manner, resorb bone as part of the ongoing process of new bone formation. We propose that myeloma cells, which exhibit characteristics of osteoclasts, home to sites in the bone marrow and initiate this bone breakdown and furthermore secrete factors required for osteoclast maturation and activity. We believe that these molecules include the recently defined molecule, termed osteoclast differentiation factor, which is normally produced by bone-producing cells known as osteoblasts. Moreover, we feel that myeloma B cells alter the function of osteoblast cells, which results in a decrease in bone formation. Finally, we propose that this disease and its associated bone defects originate from changes in the expression of a number of genes. The results from theses studies should provide a greater understanding of the way in which this B cell cancer originates and how it causes bone defects. This will lead to the development of better treatments to improve the survival of patients with MM, and will lead to therapies to prevent the associated bone complications.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