Kevin Shannon, M.D.
Auerback Distinguished Professor in Molecular Oncology
Our research is informed by human disease. We have utilized 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 cell biologic, genetic, and biochemical strategies to uncover 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.
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 myeloid malignancies, 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. We continue to utilize Nf1, Nras, and Kras mice for mechanistic studies of aberrant signaling networks and to characterize the effects of hyperactive Ras on hematopoietic stem and progenitor cell fates.
Mechanisms of Response and Resistance to Targeted Inhibitors of Signaling Molecules. Recent therapeutic efforts have focused on inhibiting downstream biochemical targets of mutant Ras such as Raf, MEK, and Akt, and many new compounds are under development or in early phase clinical trials. A general question with respect to anti-Ras therapeutics involves how to interfere with a signal transduction pathway that is integral to many normal cellular functions while achieving an acceptable therapeutic index. Answering this question will require a more complete understanding of how cells remodel signaling networks in response to chronic oncoprotein expression, and how these adaptive responses might be exploited therapeutically. Mouse models that recapitulate the mutant RAS alleles found in human cancer are invaluable tools for performing mechanistic and preclinical studies in for several reasons. First, hematopoietic cells are experimentally tractable. There are markers for all of the major differentiated subpopulations and robust in vitro assays for assaying the growth of progenitors. Hematopoietic stem cells (HSCs) and their progeny can be manipulated ex vivo and transplanted between genetically disparate individuals. This experimental flexibility provides the opportunity to generate cohorts of mice that are engrafted with the same primary tumor for conducting preclinical testing and investigating mechanisms of intrinsic and acquired drug resistance. Second, retroviral insertional mutagenesis (RIM) withMOL4070LTR provides a powerful in vivo strategy for performing forward genetic screens in mammalian cancer. In recent “proof of principle” studies, we treated primary cancers with targeted agents in vivo, isolated drug resistant clones at relapse, and analyzed pairs of sensitive and resistant clones to discover ugenes that underlie “off target” resistance to molecular therapeutics, which is emerging as a major clinical problem in patients treated with kinase inhibitors. This is a major area of ongoing interest for the lab.
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.
Last updated 10-17-2012