The IL7sigNETure project has led to:
1) the identification of novel IL7R signaling players (e.g. CK2 and sphingosine kinases); 2) the characterization of IL7R signaling idiosyncrasies in leukemic cells (e.g. STAT5 is required for IL-7-mediated viability and proliferation of T-ALL cells but, contrary to normal T cells, does not upregulate Bcl2 in malignant cells stimulated with IL-7); 3) the demonstration that IL7R signaling associated with malignancy displays similar features independently of whether it occurs in the context of IL7R mutation or IL7R overexpression.
These findings were initially disseminated by communication in prestigious, peer-reviewed scientific meetings and subsequently published in: Melão et al, Haematologica 2016; Ribeiro et al, Blood Advances 2018; De Smedt et al, Blood 2020; Perera et al, Cancers 2020; Silva et al, Blood 2021; Almeida et al, Nature Communications 2021.
Moreover, we showed that:
4) mutant IL7R cooperates with MYC in driving T-ALL in zebrafish, increasing the frequency of leukemia-initiating cells in MYC-induced tumors; 5) high IL7R expression in transgenic and knock-in mice can be oncogenic in a gene dose-dependent manner; 6) lymphoid-restricted mutant IL7R, expressed at physiological levels, establishes a pre-leukemic stage in which B-cell precursors display self-renewal ability, initiating leukemia that resembles either PAX5 P80R or Ph-like human B-ALL.
These findings were initially disseminated by communication in prestigious, peer-reviewed scientific meetings and either submitted for publication or already published in: Silva et al, Blood 2021; Almeida et al, Nature Communications 2021.
Finally, we targeted aberrant IL-7R-mediated signaling:
7) we developed anti-IL7R antibodies for the targeting of IL-7R-expressing T-ALL cells; and 8) we showed that drug targeting of the novel IL7R downstream effectors we identified (such as CK2 and sphingosine kinases) as well as well-known IL7R signaling players (such as JAK1, PI3K/mTOR, PIM1, Bcl-2 or CDk4/6) constitute valid therapeutic avenues in ALL.
These findings were initially disseminated by communication in prestigious, peer-reviewed scientific meetings and subsequently published in: Akkapeddi et al, Leukemia 2019; Hixon et al, Leukemia 2020; Melão et al, Haematologica 2016; Perera et al, Cancers 2020; Silva et al, Blood 2021; Almeida et al, Nature Communications 2021.
Importantly, the fully-human anti-IL7R antibody we developed served as the starting point for a successful application to an ERC proof-of-concept grant (ERC-2019-PoC n. 862545 IL7RsignaTHER) aiming at generating a spin-off for exploitation of new, improved anti-IL7R antibodies, a avenue that we are now actively pursuing.
Importantly, our results were also disseminated to a lay audience via our institutional website, and via social media platforms (such as twitter, facebook, instagram and LinkedIN), by presentations in high schools, through visits of high school students and other audiences to iMM (e.g. iMM open days) and by participation of several of our team members in the European Researchers’ Night, Lisbon, and the participation in similar events such as the science festival PINT OF SCIENCE. Moreover, we recently received the most prestigious Portuguese biomedical research award (Pfizer Award for Basic Biomedical research of Sociedade de Ciências Médicas de Lisboa) for the work we published in Blood in 2021. This was broadly publicized in general media and served as an excellent means of dissemination of our findings to different stakeholders and the public in general.
