Haemopoiesis is the process by which cells in the blood become committed to a specific cell type, mature and proliferate. The production of blood cells is a dynamic and constant process and if dysregulated will result in a number of different diseases and-or leukemias. Using a leukemic cell line we identified two genes, Hls5 and Hls7-Mlf1, involved in red blood cell maturation. In addition, both these genes have been implicated in cancer, Hls5 functions as a tumor suppressor and Mlf1 is associat ....Haemopoiesis is the process by which cells in the blood become committed to a specific cell type, mature and proliferate. The production of blood cells is a dynamic and constant process and if dysregulated will result in a number of different diseases and-or leukemias. Using a leukemic cell line we identified two genes, Hls5 and Hls7-Mlf1, involved in red blood cell maturation. In addition, both these genes have been implicated in cancer, Hls5 functions as a tumor suppressor and Mlf1 is associated with acute myeloid leukemia. Over-expression of either gene in immature red blood cells inhibited their development; Mlf1 had quite a profound affect on cell shape and size whereas Hls5 affected biochemical pathways with a decrease in haemoglobin production. We have identified binding partners of each of the molecules. Hls5 binds to FOG 1, a regulator of the red blood cell genes. In addition, Hls5 associates with Ubc9 and PIAS-1 - molecules involved in a novel form of gene regulation called sumoylation. Hls5 also regulates GATA-1 a key protein in red cell production. Wer have recently found that Mlf1 also regulates GATA-1. Importantly, we have demonstrated that Mlf1 binds DNA and other nuclear proteins and is able to affect gene transcription. This project will use cellular and biochemical assays as well as mouse models to elucidate the mechanisms by which these genes control the function of red blood cells.Read moreRead less
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
CD164: A Sialomucin Adhesion Molecule With Potent Growth Inhibitory Properties
Funder
National Health and Medical Research Council
Funding Amount
$242,545.00
Summary
Blood cell production in the adult mammal is normally restricted to the bone marrow. The ongoing production of blood cells is well regulated and dependent on the controlled proliferation and development of rare, multipotent precursors cells commonly termed stem cells. The blood forming stem cells exist in intimate contact with other cells and tissues that comprise the red bone marrow tissue. It is currently thought that stem cell localisation, survival and growth within the bone marrow is, in pa ....Blood cell production in the adult mammal is normally restricted to the bone marrow. The ongoing production of blood cells is well regulated and dependent on the controlled proliferation and development of rare, multipotent precursors cells commonly termed stem cells. The blood forming stem cells exist in intimate contact with other cells and tissues that comprise the red bone marrow tissue. It is currently thought that stem cell localisation, survival and growth within the bone marrow is, in part, regulated by specific interactions between the stem cells and neighbouring cells or the biochemical products of these cells. Stem cells use specific cell surface structures or cell adhesion molecules to mediate these important interactions. This project seeks to investigate the role in blood cell production, of a specific cell surface molecule, CD164, a member of a larger family of molecules with similar structural features thought to be involved in inhibition of cell growth. The main focus of the project is to identify a ligand or binding molecule for CD164. This information will allow an investigation of the consequences of binding between CD164 and its ligand by stem cells. It is proposed that the CD164-ligand interaction is one of a number of important inhibitory interactions used to regulate proliferation of stem cells. These studies will be greatly facilitated by the generation of a mouse lacking CD164.Read moreRead less