T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood cancer that preferentially affects children and adolescents. The leukemia is commonly associated with specific genetic abnormalities. Dr. Aifantis' research focuses on one particular gene, known as Notch1, which is found in more than half of T-ALL patients and which has been generally recognized as a key trigger for the induction of the disease. Dr. Aifantis and his team have recently shown, using mouse models, that not all individuals with Notch1 mutations develop leukemia. Why is that? What mechanism actually pulls the trigger? The doctor's previous research has identified another gene, the pre-T-cell receptor, as possibly involved. This research project made possible by The G&P Foundation will use mouse models to try to answer this question by unraveling the relationship between the two genes. Better understanding of the pathways between these genes could lead to the design of new treatments for T-ALL patients.

Umbilical cord blood (UCB) collected from healthy newborns is an alternative source of blood-forming stem cells and UCB transplant is a very promising treatment strategy in children with leukemia. However, early experience in UCB transplant in adults has not been successful in many patients due to insufficient number cells in a single UCB collection (known as a UCB "unit"). Early experience in a new way of doing UCB transplants in adults by combining UCB collections from two different babies has been encouraging. This proposal will further investigate these "double" unit UCB transplants after high dose therapy to treat patients with leukemia and myelodysplasia, and UCB will be studied in the laboratory in order to better understand how these "double" unit transplants work. Finally, the extent to which UCB extends access to transplant in patients without other suitable donors, and what patients remain without donors, will be analyzed. This work is important as successful UCB transplant in adolescents and adults will significantly extend access to curative therapy for many patients with cancers of the blood and bone marrow.

Epstein-Barr virus (EBV) infections are associated with a number of types of human cancer, including Burkitt lymphoma, nasopharyngeal carcinoma, and Hodgkin's lymphoma. EBV carries a number of viral genes whose products are known to result in increased cell growth and/or decreased cell death, both of which contribute to the growth of cancer cells. In Burkitt lymphoma the role of EBV in cancer is unclear as the virus does not express those genes known to stimulate cell growth in the laboratory. However, the ability of Burkitt lymphoma cells to cause tumors in an experimental model is strictly dependent on the presence of the virus and is in part due to expression of two small viral RNAs (EBERs). These RNAs, unlike most RNAs, do not result in production of a protein. Rather their function is accomplished as an RNA molecule. Dr. Ruf's goal is to understand how the virus causes cancer by investigating the mechanisms of action of the EBERs. Dr. Ruf and her team are investigating what cellular gene products are required for EBER function and how the EBERs alter the normal function of these genes to benefit the virus. Dr. Ruf anticipates that the knowledge they gain in these studies will be applicable to all EBV-dependent tumors, as well as to their understanding of the role of the EBERs in maintaining infection in healthy virus carriers. Identification of how this virus causes cancer will lead to targets for future treatment of developing and established tumors and perhaps preventive therapies. Additionally, their work aims to contribute to a relatively new field of research relating to RNA molecules in general function and how they can influence the growth and survival of cells.

Dr. Sternberg’s laboratory is committed to the development of therapeutic strategies for leukemia through knowledge of aberrant information signaling within the cancer cell. The generation of leukemias is caused in many instances by mutation of rogue oncogenes that disrupt normal cell signaling. Two of these, the NPM and FLT3 genes, are among the most commonly mutated targets in patients with acute myelogenous leukemia (AML).

In this effort Dr. Sternberg’s team is exploring the mechanism of leukemia induction by the mutant NPM and FLT3 gene products. In particular, they focus on the conversion of genetic information in the form of messenger RNA into abnormal protein expression. Their hypothesis is that mutant NPM and FLT3 usurp this process, termed translation, in patients with AML. They are using state-of-the-art gene expression profiling technologies to understand how mutant NPM and FLT3 alter normal translation within a cancer cell. Moreover, Dr. Sternberg’s team will develop models to validate the functional role of particular translational targets in the pathogenesis of AML. They anticipate that the insights gained from this study will inform new prognostic and therapeutic strategies for the treatment of these frequently lethal neoplasms.

In the last decade the prevention of cancer through the use of chemopreventive agents has become a possibility. We are now faced with how best to begin to assess the effectiveness of potential agents for a variety of cancer sites. With this in mind Dr. Visvanathan plans to explore whether broccoli sprouts, a potential preventive agent against breast cancer alters estrogen metabolite levels in both breast tissue and urine. This study has direct relevance to long term female survivors of Hodgkin’s lymphoma given their increased risk of breast cancer as a result of radiation treatment. At present they are grappling with how to best to screen these young women for breast cancer and reduce their long term risk of breast cancer. From Dr. Visvanathan’s experience, this is clearly a group in need of better preventive strategies. It is unknown whether broccoli sprouts may protect the breast from the long term effects of radiation damage. However in animal models the topical application of a broccoli sprout extract reduced the size of skin cancers. The identification of markers for breast cancer such as estrogen metabolites may also help identify those women more likely to develop breast cancer among female survivors of Hodgkin’s lymphoma. These women could then be targeted with more aggressive screening and risk reduction options.

Programmed cell death, also called apoptosis, is a normal process that the body uses to rid itself of damaged cells. Cancer cells acquire the ability to evade this process, allowing them to live too long, as well as to resist therapeutic treatments such as chemotherapy and radiation. Cancer cells have genetic defects in this normal cellular “suicide” program that governs cell death and survival. The discovery of the BCL-2 family of genes uncovered the underlying genetic mechanism of this regulation, as well as an entirely new class of oncogenes: those that govern cell death rather than cell proliferation. The founder of this family, the Bcl-2 gene, was found to be located at the chromosomal breakpoint of t (14; 18)-bearing human B-cell lymphomas. Since then, a whole family of related proteins, called the BCL-2 family after its founding member, has been discovered that regulates cell death. My work showed that the pro-death BCL-2 family member BID is important in preventing cancer development in the blood cells of mice (leukemia).

The best model to test the role of a gene in normal development is an animal model in which the gene of interest has been disrupted. The deletion of BID prolongs the lives of myeloid cells, fostering the accumulation of additional genetic mutation and promoting the development a fatal disorder resembling the human disease chronic myelomonocytic leukemia (CMML). These studies reveal that BID plays a critical role in preserving genomic integrity, maintaining myeloid homeostasis (metabolic equilibrium), and suppressing tumor growth and normal immune (myeloid cell behavior). The occurrence of cancer in the BID-deficient mice underscores the importance of apoptotic control in the development of chronic leukemia and related disorders.

Tumor progression is a multi-step process in which a succession of genetic changes leads to uncontrolled cell growth, a hallmark of cancer. Paradoxically, many of the agents currently used to treat cancer can accelerate the acquisition of these genetic changes in the event that the treated cells do not die, potentially leading to further tumor progression and/or resistance to therapy. Dr. Zinkel’s current studies are focused on identifying the proteins that interact with BID following this DNA damage and how BID functions during this process. Dr. Zinkel’s goal is to uncover the genes and the proteins that direct the decision of a cell to repair its DNA or to die, providing important clues in the search for therapeutic targets.