Project Title: Mechanisms of Sensitivity and Resistance to Molecularly Targeted Leukemia
Principal Investigator: Ross Levine
Project Abstract: Our studies are aimed at assessing how mutational patterns modulate resistance to anti-leukemic therapies, including therapies that target IDH1/2 and FLT3 kinase signaling. We use an integrative analysis of therapeutic studies in mouse leukemia models and in patient samples to elucidate novel genetic modulators of response to anti-leukemic targeted therapies.

Project Title: RTEL1 mutations in Hoyeraal Hreidarsson Syndrome
Principal Investigator: John Petrini
Project Abstract: This proposal is focused on understanding the mechanistic basis of related severe bone marrow failure disorders: Dyskeratosis Congenita and Hoyeraal Hriedarrson syndrome. We have discovered that the underlying mutation is a founder allele with the potential to pose a public health concern in the Ashkenazi Jewish population. The data we obtain in this study will provide fundamental new insights regarding the maintenance of genome integrity and its relationship to the onset and progression of disease associated with aging and the development of proliferative tissues.

Project Title: New mouse models of colorectal carcinoma to study genetic determinants of cancer progression and maintenance
Principal Investigator: Scott Lowe
Project Abstract: Metastatic colorectal carcinoma (CRC) is a leading cause of cancer cell death, but model systems that accurately reflect the genetics and pathological features of the disease have been lacking. Project 3 combines powerful genetic tools and intestinal organoid transplantation to produce mouse models that recapitulate all stages of the adenoma - carcinoma - metastasis progression. These models are being used to study the biological and molecular mechanisms of CRC initiation and progression as well as to evaluate new therapeutic concepts.