Leukemia, a cancer of the blood cells, begins in the bone marrow—the body’s blood cell factory. It causes the stem cells in the bone marrow, that usually develop into normal white blood cells (the body’s defense system against infection), to instead make abnormal immune cells that can’t fight infections. Eventually, these abnormal immune cells crowd out the normal blood cells. Without a sufficient population of functional white blood cells, leukemia patients develop anemia, bleeding, and infections.
Recent research has shown that in addition to these abnormal white blood cells, leukemia patients also have a small population of cells called leukemia stem cells, or tumor-initiating cells (TICs). These are the original initiators of the excessive abnormal leukemia cells. Scientists express certain surface proteins, which allow them to evade treatments that kill leukemia cells, and then later go on to cause a relapse. One of the goals in leukemia stem cell research is to find ways of destroying these tumor-initiating leukemia cells. 
Leukemia is an often-fatal disease; one especially deadly form, acute myeloid leukemia (AML), has a 75% death rate within just 5 years of diagnosis. Although tremendous advances have been made in the treatment of childhood leukemia, 50% of adults diagnosed with leukemia will die of the disease.
Treatment for leukemia can be physically and emotionally agonizing, as well as financially devastating. The average cost of one round of chemotherapy is approximately $150,000. Bone marrow transplants can cost between $100,000 and $250,000.  Moreover, chemotherapy and radiation take an enormous toll on the body, causing serious side effects. Chemotherapy and radiation kill cancerous cells, but they also kill healthy cells in the process, further compromising the body’s already-weak immune system.
Chemotherapy and radiation have long been the standard, aggressive treatments for leukemia and other types of cancer. However, these treatments are not always fully effective, as they sometimes fail to get at the root of the problem—the leukemia stem cell—and relapse can occur. With the support of Proposition 71 and CIRM funding, scientists have pinpointed a significant cause of leukemia’s frustrating ability to recur. Hopefully, their work will lead to therapies that fully eliminate cancerous cells in leukemia patients, bringing the rate of relapse to zero.
CIRM has awarded more than $94 million in funding to leukemia-related research, including two Disease Team grants, which seek to receive FDA approval to initiate a human clinical trial within four years of the award.
Drs. Catriona Jamieson and Dennis Carson of UC San Diego, in collaboration with Dr. John Dick at the University Health Network in Toronto, Canada, have discovered a way to target the cause of leukemia’s ability to come out of remission. Their research has found a way to pinpoint these cancer stem cells, which could allow for the development of specialized therapies beyond chemotherapy and radiation to defeat leukemia.
Leukemia stem cells, a type of tumor-initiating cell or “cancer stem cell,” can be thought of as the “evil twins” of normal tissue stem cells, with similar properties, but damaging effects. Like ordinary stem cells, cancer stem cells are able to self-renew and produce more copies of themselves; their danger lies in their ability to make an unlimited amount of cancerous cells. Cancer stem cells evade cues from the body that normally regulate stem cell behavior, allowing them to divide unchecked. This property differentiates them from normal tissue stem cells that respond to signals from the body. While normal stem cells develop into whole organs, cancer stem cells form whole cancerous tumors. Because these cancer stem cells are able to evade the body’s natural immune response to mutated or cancerous cells, they are often able to evade chemotherapy and radiation. Even if just a small number of cancer stem cells survive, over time, they can multiply and ultimately develop into another tumor. With CIRM and Proposition 71 support, Drs. Jamieson, Carson, and Dick are working to develop of a Highly Active Anti-Leukemia Stem Cell Therapy (HALT) that targets the harmful leukemia stem cells, but leaves healthy cells unaffected. Their progress has led to the discovery of a signature molecule that is present in the leukemia stem cells, but not in normal cells.
Proposition 71 and CIRM funding has led to several human clinical trials for leukemia and blood disorders. Dr. Jamieson has initiated human clinical trials for myelofibrosis, a severe blood disorder, at UC San Diego. The findings from these early myelofibrosis trials served as the impetus for Dr. Jamieson’s idea to expand these trials to include another rare blood disorder, called polycythemia vera. Polycythemia vera is a rare blood disorder that causes overproduction of red blood cells; in 10-15% of cases, it develops into Acute Myeloid Leukemia. Trials for polycythemia vera have completed Phase 3 studies, and the therapeutic candidate is in the process of being commercialized by a major pharmaceutical company.
At Stanford University, Dr. Irving Weissman, in collaboration with the University of Oxford and collaborative funding from the United Kingdom, has also made pivotal breakthroughs in the study of leukemia. Research in Dr. Weissman’s lab has led to the discovery that most—if not all—cancer cells consistently display high levels of a protein, called CD47, on the surface of their cell membrane. This CD47 protein acts as a “don’t eat me” signal to the body’s natural immune defense against cancer—immune cells called macrophages. These cells are normally responsible for destroying or “eating” damaged or mutated cells. To thwart this evasion mechanism, Dr. Weissman and his colleagues have developed an antibody molecule, called anti-CD47, which binds specifically to CD47 and mask its presence on cancer cells. When cancer cells are covered with anti-CD47, they once again become vulnerable to the killing action of macrophages. Moreover, Weissman’s team also found that once the cancer cells are digested, the macrophages can then stimulate another important arm of the immune system: T-cells. These T-cells are then specifically activated against the tumor cells, ultimately achieving an anti-cancer “vaccination” effect.  Human clinical trials using this approach to treat AML are currently underway in the United Kingdom, and are also proceeding at Stanford University. If these initial safety trials are successful, Phase II trials (designed to test efficacy) will commence in 2016, expanding to treat other forms of cancer, including adult and pediatric brain tumors.
Selected disease and research progress information provided by the California’s stem cell research funding agency, the California Institute for Regenerative Medicine (CIRM). Visit www.cirm.ca.gov for more updates.
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3. Nature (2011) Evolution of human BCR-ABL1 lymphoblastic leukaemia-initiating cells. (PubMed: 21248843)
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