Walter and Eliza Hall Institute of Medical Research

About: Walter and Eliza Hall Institute of Medical Research is a nonprofit organization based out in Melbourne, Victoria, Australia. It is known for research contribution in the topics: Antigen & Immune system. The organization has 5012 authors who have published 10620 publications receiving 873561 citations.

bcr-abl, the hallmark of chronic myeloid leukaemia in man, induces multiple haemopoietic neoplasms in mice.

Abstract: The chromosome translocation forming the hybrid bcr-abl gene is thought to be the initiating event in chronic myeloid leukaemia (CML) and some cases of acute lymphoblastic leukaemia. To assess the impact of bcr-abl upon haemopoiesis, lethally irradiated mice were reconstituted with bone marrow cells enriched for cycling stem cells and infected with a bcr-abl bearing retrovirus. The mice developed several fatal diseases with abnormal accumulations of macrophage, erythroid, mast and lymphoid cells, and marked strain differences in disease distribution and kinetics. Some mice exhibited more than one neoplastic cell type and, in some instances, these were clonally related, indicating that a progenitor or stem cell had been transformed. While classical CML was not observed, the macrophage tumours were accompanied by a mild CML-like syndrome, probably due to myeloid growth factor production by tumour cells. The erythroid and mast cell diseases were rarely transplantable, in contrast to the macrophage tumours and lymphomas, but all disease types displayed limited clonality. These results establish that bcr-abl confers a proliferative advantage on diverse haemopoietic cells but complete transformation probably involves additional genetic changes.

The scl gene product is required for the generation of all hematopoietic lineages in the adult mouse.

Abstract: Homozygosity for a null mutation in the scl gene causes mid-gestational embryonic lethality in the mouse due to failure of development of primitive hematopoiesis. Whilst this observation established the role of the scl gene product in primitive hematopoiesis, the death of the scl null embryos precluded analysis of the role of scl in later hematopoietic development. To address this question, we created embryonic stem cell lines with a homozygous null mutation of the scl gene (scl-/-) and used these lines to derive chimeric mice. Analysis of the chimeric mice demonstrates that the scl-/- embryonic stem cells make a substantial contribution to all non-hematopoietic tissues but do not contribute to any hematopoietic lineage. These observations reveal a crucial role for the scl gene product in definitive hematopoiesis. In addition, in vitro differentiation assays with scl-/- embryonic stem cells showed that the scl gene product was also required for formation of hematopoietic cells in this system.

Peripheral deletion of self-reactive B cells

Abstract: B LYMPHOCYTES are key participants in the immune response because of their specificity, their ability to take up and present antigens to T cells, and their capacity to differentiate into antibody-secreting cells. To limit reactivity to self antigens, autospecific B cells can be functionally inactivated or deleted1–4. Developing B cells that react with membrane antigens expressed in the bone marrow are deleted from the peripheral lymphocyte pool4–6. It is important to ascertain the fate of B cells that recognize membrane autoantigens expressed exclusively on peripheral tisues because B cells in the peripheral lymphoid organs are phenotypically and functionally distinct from bone-marrow B cells7–9. Here we show that in immunoglobulin-transgenic mice, B cells specific for major histocompatibility complex class I antigen can be deleted if they encounter membrane-bound antigen at a post-bone-marrow stage of development. This deletion may be necessary to prevent organ-specific autoimmunity.

In Vitro Colony Formation by Normal and Leukemic Human Hematopoietic Cells: Characterization of the Colony-Forming Cells

Abstract: Agar cultures of blood and marrow cells were used to determine the nature and frequency of granulocytic progenitor cells (in vitro colony-forming cells) in 133 patients with various hematologic diseases, including 33 with acute and 17 with chronic myeloid or myelomonocytic leukemia. Cultures from patients with acute myeloid leukemia (AML) in relapse or in the acute transformation phase of chronic myeloid leukemia (CML) were characterized by lack of normal colony formation and either complete absence of in vitro proliferative capacity or production of large numbers of small clusters composed of poorly differentiated cells. Patients with CML had greatly increased numbers of colony-forming cells particularly in the blood, and these were identified as myeloblast-like cells with a cloning efficiency of at least 60%. The leukemic cells grown from every patient in this study were responsive to stimulation by the specific regulator, colony-stimulating factor, supplied in culture by underlayers of normal peripheral blood cells. Leukemic colony-forming cells had an abnormally light buoyant density and low suiciding index with tritiated thymidine. Remission in both AML and CML was associated with a return to normal in the location, incidence, buoyant density, and suiciding index of colony-forming cells. Density separation may make it possible to separate normal frol'!'l leukemic progenitor cells for therapeutic purposes.-J Natl Cancer Inst 50:603-623,1973.