Leukemia represents a variety of blood cancers that originate in bone marrow where blood cells are produced. Bone marrow from leukemia patients is widely populated with leukemia cells. A pathologist makes a diagnosis of leukemia by looking at blood and marrow films. Current successful treatments focus on eliminating the leukemic blood cells, and in some cases are followed by bone marrow transplantation. Bone marrow contains many different types of stem cells, which are regenerative cells. Bone marrow continually produces new blood cells—red cells, white cells, and platelets—throughout a person’s life. Supporting cells in the bone marrow have been known for over a century; these cells are called stromal cells (as the word “stroma”, in Latin, means mattress). Stromal cells have recently proven to be connective tissue or mesenchymal stem cells. Like all stem cells, the numbers of these cells are limited in bone marrow, but still they have the potential to populate the colonies of cells found throughout the body. Stromal cells thus constitute the principal components of various microenvironments—not only of marrow but also of breast, ovary, lymph nodes, etc. Scientists have studied and developed well-established cell growth systems for these easily reproduced cells to determine the function of both healthy and diseased cells and ultimately to be able to modify or destroy diseased cells. By studying not just cancer cells (i.e., the seeds) but also their microenvironments (i.e., the soil in which cancer “seeds” germinate, live and thrive) and by establishing new well-characterized stromal cell lines, scientists expect to identify the switches that turn on/off various kinds of diseases of the blood and other organs.
In this application, the investigator proposes to establish unique stromal cell lines from a spectrum of blood disorders. The research team proposes to grow, expand, and isolate marrow stromal cells from patients having various types of leukemia, multiple myeloma, myelodysplastic syndromes, and aplastic anemia, and then immortalize them using state-of-the-art technologies. Once established and characterized, these immortalized cell lines will be made widely available to the scientific community. This research will enable scientists to conduct their investigations using standardized cells, thus advancing the search for causes and treatments of devastating diseases. Because of the potential of stromal cells to develop into a variety of connective tissues, like muscle, bone, fat and even nerve cells, the generation of these cell lines offers virtually unlimited practical research opportunities to investigators in many different disciplines in California and throughout the world.
Bone marrow stromal mesenchymal stem cells are the chief component of the marrow microenvironment, which controls the production of normal blood cells as well as promotes the development of leukemia, a deadly disease that represents a variety of blood cancers originating in the marrow. Like all other cancers, leukemia is a purposeless, progressive proliferation of blood cells, growing out of control and ultimately killing the patient if untreated, and in some unfortunate cases even if treated. According to the Leukemia & Lymphoma Society’s “Facts 2007-2008”, new cases of leukemia, Hodgkin and non-Hodgkin lymphoma, and myeloma will account for nearly 9.4 percent of the 1,444,920 new cancer cases diagnosed in the US this year. Every five minutes someone in the US is diagnosed with a blood cancer, and every 10 minutes someone dies from this terrible disease. Furthermore, according to Cancer Statistics 2007, there were an estimated 4,610 new cases of leukemia and an estimated 2,150 deaths from leukemia in California, as compared to 44,240 new cases of leukemia and 21,790 deaths from leukemia in the US in 2007. The broad objectives of our proposed studies thus are to understand the role of the marrow microenvironment in leukemia development and conversely the deleterious impact of leukemia cells on stromal cells and their ability to support normal blood cell production, which is almost always compromised in leukemia patients. Because marrow stromal cells by nature represent adult mesenchymal stem or progenitor cells (MPCs) with multi-lineage differentiation capacity, they offer promising potential for regenerative medicine.
One of the largest barriers to advancing stem cell biology, including studies of MPCs and ultimately their application to therapy, is the establishment of well-characterized, immortalized cell lines to promote investigational standardization. Moreover, MPCs are not merely multi-potential but they are also multi-functional in the physiological sense, a fact not adequately appreciated. Functional properties of stromal cells include the following. a) MPCs are crucial to normal blood cell production. b) MPCs likely influence the genesis and progression of chronic blood diseases. c) MPCs’ role in leukemia is viewed as part of an emerging paradigm by which neighboring non-malignant cells regulate growth and development of malignant cells. d) MPCs have anti-proliferative and immunomodulatory properties. Still, little is known about the molecular mechanisms governing the critical biological roles of MPCs. MPC lines should, therefore, be valuable experimental tools. In addition to being useful for regenerative medicine purposes, they are critical for investigating various functional properties of stromal cells, including their roles in regulating leukemia cell growth and progression. This research will result in the development of novel diagnostic tools and treatment modalities for cancer patients in California and throughout the world.