This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. An emerging view of cancer suggests that corruption of normal stem cells can contribute to tumor formation, progression, or therapy resistance. Indeed cancer stem cells have been identified in some tumors, but in most cases such cells, while postulated, have not yet been identified or characterized. Important challenges in understanding cancer will be to identify cancer stem cells, to determine their relationship to normal stem cells, and to evaluate whether cancer stem cells from different malignancies exhibit common characteristics. Another hallmark of cancer is chromosome instability. While characteristic chromosome abnormalities have been documented for numerous cancers, and are often of clinically predictive value, their origin remains unclear. Both stem cell biology and chromosome instability are important (and likely related) issues pertaining to clinical management of cancer, Therefore, the objectives of this proposal are to determine whether derangement of normal stem cell properties is related to lymphoma formation, and to identify the mechanisms behind chromosome instability, especially in normal or cancer stem cells. To achieve these objectives we are exploiting a mouse model of Richter s syndrome, a disease leading to conversion of chronic leukemia to acute, aggressive lymphoma associated with therapy resistance and rapid clinical deterioration. In this mouse model, DNA repair deficiency produces chromosome instability, leading to formation of lymphomas with characteristic chromosomal rearrangements. With this system we will identify and characterize the cancer stem cell population, and determine the molecular mechanisms driving chromosome instability. This work will be important for developing improved diagnostic methods and novel cancer therapies.
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