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Auerback Distinguished Professor in Molecular Oncology Director, UCSF Medical Scientist Training Program Interim Chair of the Department of Pediatrics (415) 476-7932 Helen Diller Building 1450 3rd Street Room 263 San Francisco, CA 94158 |
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Our research is informed by human disease. We have utlilized inherited predispositions to myeloid leukemia and recurring cytogenetic alterations in leukemia cells as entry points to search for genetic lesions that contribute to leukemogenesis. We model these mutations in the mouse, and use a combination of strategies to interrogate murine and human cells to understand proteins and pathways, which are crucial for hematopoietic growth control and are undermined in leukemia. We are actively engaged in exploiting genetically engineered strains of mice as a tractable experimental system for testing novel therapeutic strategies. This research benefits from the collegial and interactive environment at UCSF and from collaborations with Scott Kogan, Nigel Killeen, Kevan Shokat, Tyler Jacks, Gideon Bollag, Michelle Le Beau, Scott Lowe, Jim Downing, Lynda Wolff, and Luis Parada and other investigators. |
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Kevin Shannon M.D. |
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Shannon Lab |
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The Ras Pathway in Myeloid Leukemogenesis. We have investigated the association of neurofibromatosis, type 1 (NF1) with childhood leukemia in primary cells and in mice with a targeted disruption at the Nf1 locus. Children with NF1 are predisposed to juvenile myelomonocytic leukemia (JMML) and other myeloid malignancies. Our studies of children with JMML showed that NF1 functions as a tumor suppressor gene that restrains the growth of immature myeloid cells by negatively regulating Ras signaling. We also found that somatic inactivation of Nf1 in hematopoietic cells induces a myeloproliferative disease (MPD) that models JMML and chronic myelomonocytic leukemia (CMML), and have performed biologic and preclinical studies in this strain. We have also used Mx1-Cre strain to activate latent Kras and Nras oncogenes in hematopoietic stem cells. These mice also develop MPD, and we are investigating mechanisms of leukemogenesis at the genetic, cellular, and biochemical levels. In recent experiments, we injected Nf1, Kras, and Nras mutant mice with the MOL40470LTR retrovirus to identify genes that cooperate with hyperactive Ras signaling in progression to acute leukemia and modulate drug responsiveness and resistance. We continue to utilize Nf1, Nras, and Kras mice to map aberrant signaling networks, to investigate the effects of hyperactive Ras on hematopoietic stem and progenitor cell fates, and to test novel therapeutic strategies.
Chromosome 7 Deletions in Leukemia. The leukemias that develop in patients with genetic predispositions such as NF1 and Fanconi anemia or in the context of medical exposure to mutagens frequently show chromosome 7 deletions (monosomy 7) or loss of the long arm del(7q). Major efforts in the lab focus on cloning and characterizing candidate tumor suppressor genes from a commonly deleted interval of chromosome band 7q22, and using chromosome engineering strategies for engineering large segmental deletions in the mouse. |
