Biomedical Sciences Graduate Program | University of California, San Francisco

We have 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 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. We are also working to model the effects of leukemia-associated PTPN11 mutations in the mouse. Cells from Kras and Nf1 mutant mice also provide a tractable system for screening novel therapeutics and for investigating mechanisms of chemotherapy response and resistance. To uncover how lossof chromosome 7 contributes to leukemia, we are interrogating a 2.5 Mb commonly deleted segment of chromosome band 7q22 found in myeloid malignancies. In addition to these studies in human patients, we are 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. 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).