The oncogenic IL7R is known to activate three pathways in acute lymphoid leukemia (ALL): JAK/STAT, PI3K/AKT/mTOR and RAS/MEK/ERK. However, the activation of RAS/MEK/ERK has not been characterized. Mutations in RAS/MEK/ERK are recurrent in human ALL (7/15 cases of ALL with mutations in the IL7R have cooccurring mutations in genes of the RAS/MEK/ERK pathway) and in murine ALL originating from our mouse model of the oncogenic IL7R. Moreover, the combined use of RAS and PI3K inhibitors has a synergistic effect against ALL carrying IL7R or JAK mutations. This suggest a collaboration between the RAS/MEK/ERK with the JAK/STAT and/or PI3K/AKT/mTOR pathways for the development of ALL. In this project we aim to characterize the mechanism of activation of RAS/MEK/ERK by the oncogenic IL7R. Primary murine ALL samples from the oncogenic IL7R mouse model will be used to evaluate possible correlations between activation of the JAK/STAT, PI3K/AKT/mTOR and RAS/MEK/ERK pathways. Site directed mutagenesis of the IL7R receptor and co-immunoprecipitation assays will be used to dissect the participation of IL7R's residue Y449, JAK1, PI3K, and SHC in RAS activation by the oncogenic and wild type IL7R. Inhibitor of RAS/MEK/ERK will be tested in vivo against different murine ALLs, alone or in combination with other agents, to evaluate its potential use in ALL therapy.
News published in Agência FAPESP Newsletter about the scholarship: