Dr.
Kevin Shannon
 is the Auerback Distinguished Professor of Molecular
Oncology and Leader of the Program in Hematopoietic Malignancies in the
UCSF Comprehensive Cancer Center. Dr. Shannon has held leadership positions
in the American Society of Hematology, Children’s Cancer Group,
the Leukemia and Lymphoma Society of America, and the American Cancer
Society. He is the Co-Chair of the Steering Committee of the National
Cancer Institute’s Mouse Models of Human Cancer Consortium. Among
Dr. Shannon’s honors and awards are two Navy Commendation Medals,
the Nycomed Research Award of the International Society for Pediatric
Oncology, and the American Academy of Pediatrics Award for Excellence
in Research.
The Shannon lab has exploited inherited predispositions and recurring
cytogenetic alterations as entry points to search for genetic lesions
that contribute to leukemogenesis. This work has converged on the Ras
pathway and on the role of chromosome 7 deletions (monosomy 7) in leukemogenesis.
Our research uncovered mutations in the NF1 and PTPN11 genes in juvenile
myelomonocytic leukemia (JMML) and other myeloid malignancies. NF1, which
encodes a GTPase activating protein for Ras, functions as a tumor suppressor
gene. The PTPN11 gene encodes SHP-2, a non-receptor protein tyrosine phosphatase
that relays signals from activated growth factor receptors to Ras and
other effectors. Somatic PTPN11 mutations exist in 35% of JMML samples
that are predicted to activate phosphatase activity by disrupting the
interaction between the N-SH2 and the PTP domains of SHP-2. In recent
experiments, we harnessed the interferon-inducible Mx1-Cre recombinase
to develop a tractable mouse model of MPD by inactivating Nf1 in hematopoietic
cells. The subacute nature of the Nf1-associated disease is attractive
for performing forward genetic screen to identify genes and pathways that
are mutated during transformation from chronic to acute leukemia. Based
on our work in children with inherited predispositions, we hypothesized
that an oncogenic RAS mutation could initiate myeloid leukemia, and recently
showed that this was true in studies in which we induced the expression
of a latent Kras oncogene in hematopoietic cells. The ability to temporally
regulate Nf1 inactivation or Kras activation now enables us to examine
the biochemical and cellular effects of hyperactive Ras in primary hematopoietic
cells. Cells from Kras mutant mice also provide a tractable system for
screening novel therapeutics.
Many researchers are investigating targeted small molecule cancer therapeutics.
In addition to directly inhibiting proteins that are deregulated in cancer
cells, the Shannon lab is testing the idea that targeted therapeutics
can enhance the efficacy of traditional agents. The underlying rationale
is simple. Exposure to mutagenic agents is known to activate damage control
and survival pathways in cancer cells that are likely to contribute to
chemotherapy resistance. In collaboration with Scott Lowe (Cold Spring
Harbor), we have launched a major effort to use our genetically engineered
mouse models to understand the cellular responses of primary myeloid leukemia
cells to Ara-C and doxorubicin, with the goal of identifying pathways
that modulate resistance in vivo. The long-term goal of this work is to
use small molecule inhibitors to disable these pathways and thereby enhance
the therapeutic index of chemotherapeutic drugs.
Overall, monosomy 7 and del(7q) are found in ~10% of de novo myeloid
malignancies and portend a poor prognosis. The Shannon lab has cloned
~20 known and novel genes from a 2.5 Mb commonly deleted segment of chromosome
band 7q22 found in myeloid malignancies. However, mutational analysis
has not uncovered “second hits” in any candidate gene. We
are cloning additional genes from this interval as well as exploiting
recent technical advances to attack this problem in the mouse. This strategy
involves creating a large deletion that models the loss of 7q22 found
in human leukemias. We have generated cyotgentically normal ES cell clones
by sequential gene targeting of boundary loci, and are generating chimeric
mice. This strain will be exceptionally valuable for determining if the
2.5 Mb segment of human 7q22 that we have implicated from studies of human
leukemias contains a tumor suppressor that undergoes homozygous inactivation,
or if this myeloid tumor suppressor functions through a mechanism that
involves gene dosage (haploinsufficiency).
For additional information on the Shannon lab and a list of recent publications,
please visit the website.
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