Identification and functional analysis of stem cells in acute lymphoblastic leukemia
Acute lymphoblastic leukemia (ALL), a malignancy derived from lymphocyte precursors in the bone marrow, is by far the most frequent type of cancer in children and is seen throughout adulthood as well. In 2006, 3,930 patients were newly diagnosed with leukemia in the United States, the majority of them are children and teenagers. Therapeutic advances over the past 40 years have made ALL a curable disease in many cases. In the majority of patients, the initial therapy is successful in eradicating the leukemia cells entirely. However, in some patients, a small number of leukemia cells survive, become resistant to the treatment and the disease recurs. When this happens, it is termed a “relapse” of the leukemia and very often, relapse leukemia cannot be treated successfully.
Cutting edge research now focuses on the understanding of the few drug-resistant leukemia cells that initiate the leukemia and that may eventually cause the relapse. These cells are termed “leukemia stem cells” because they share their capacity of self-renewal with normal stem cells. In addition, leukemia stem cells (like normal stem cells) can give rise to various distinct progeny populations of the leukemia. While as few as 20 leukemia stem cells are enough to induce full-blown leukemia in mice, more than 50,000 “regular” leukemia cells are otherwise needed to induce the disease.
The overall objective of this proposal is the identification of the “Achilles heel” of these leukemia stem cells. Our proposal focuses on the concept to force the leukemia stem cells to mature so that they eventually lose their stem cell features and become more sensitive to drug-treatment. Depending on the outcome of the studies we are proposing in leukemia animal models, we plan to develop a novel therapeutic approach for the treatment of ALL that will focus on leukemia stem cells. Our proposal brings together a team of investigators with expertise in patient care, drug development, basic science and structural chemistry. This multidisciplinary approach allows us to translate the identification of stem cell-like signaling pathways in ALL cells into a novel therapeutic agent to specifically target these pathways in patients towards a cure for otherwise drug-resistant ALL.
Acute lymphoblastic leukemia (ALL) represents the malignant outgrowth of a transformed lymphocyte progenitor within the bone marrow. For yet unknown reasons, ALL is particularly frequent in children and teenagers and represents by far the most frequent type of cancer in childhood and adolescence. According to a statewide survey of the California Cancer registry and California Department of Health Services, every year 680 children and teenagers under the age of 20 are newly diagnosed with ALL (ICCCIa) in California. This corresponds to an annual age-corrected incidence of 6.2 new patients with ALL among 100,000 Californians. This almost corresponds to the half of the total annual incidence for all types of childhood cancer in California, which is at 14.5 per 100,000 inhabitants.
Over the past four decades, constant improvement of cytotoxic drug treatment has made ALL a curable disease in many cases. In fact, about 60 percent of children and about 35% adults with ALL can be cured during the initial course of chemotherapy. However, in many patients, a small subset of particularly drug resistant cells persist and initiate the recurrence of leukemia. Relapse leukemia is typically even more drug resistant than the primary tumor, which makes it particularly difficult to treat patients with ALL relapse successfully. In this case, there are only few treatment options including highly aggressive chemotherapy often followed by allogeneic bone marrow stem cell transplantation. However, aggressive chemotherapy has severe side-effects. In addition, consequences of allogeneic bone marrow transplantation may include the requirement of life-long immunosuppression to prevent life-threatening graft versus host disease. For this reasons, California State legislation recently initiated a state-wide bank for umbilical cord blood. Assembly bill 34, introduced by assembly member Anthony J. Portantino became effective on July 1st 2007. The California Cord Blood Bank expands the pool of stem cell preparations that are available for transplantation and even allows for transplantation of healthy autologous stem cells.
In an approach to even prevent the development of relapse of ALL and to avoid extensive side effects of aggressive chemotherapy, we propose a strategy that will target leukemia stem cells in ALL. We hypothesize that complete eradication of leukemia stem cells will drastically reduce the frequency of ALL relapse, improve overall survival of ALL patients, increase the quality of life of the cancer survivors, reduce the burden of chemotherapy-related side-effects and shorten the duration of therapy. Our proposal aims to lay the foundation for the development of a new generation of stem cell-targeted agents that will help to achieve these goals.