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IL-7/IL-7R signaling networks in health and malignancy

Periodic Reporting for period 4 - IL7sigNETure (IL-7/IL-7R signaling networks in health and malignancy)

Reporting period: 2020-03-01 to 2021-08-31

Interleukin 7 (IL7) and its receptor (IL7R) are essential for normal T-cell development and function. However, they can also promote autoimmunity, chronic inflammation and cancer. We and others have shown that patients with T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematological cancer, and with high risk B-cell ALL (B-ALL) can display IL7R gain-of-function mutations leading to downstream signaling activation and cell transformation. Despite the biological relevance of IL7 and IL7R, the characterization of their signaling effectors and the knowledge of whether they can trigger leukemia development remain limited.
As such, we proposed to:
1) Establish the IL-7/IL7R signaling networks in health and malignancy;
2) Characterize the impact of aberrant IL7R signaling in hematopoiesis and leukemogenesis;
3) Widen our therapeutic arsenal against ALL, and especially T-ALL, by selectively targeting aberrant IL7R-mediated signaling.
In doing so, we wished to understand how IL7/IL7R signaling putatively promotes ALL development and establish novel strategies to better and more selectively target the leukemic cells.
Our studies have led to the identification of novel IL7R signaling players, the characterization of IL7R signaling idiosyncrasies in leukemic cells, and 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. Notably, we have shown that both IL7R mutational activation as well as high levels of IL7R expression can initiate leukemia development in animal models, leading to tumors that display striking similarities to human ALL. Finally, we efficiently targeted IL-7R-expressing leukemias by developing a fully-human anti-IL7R antibody and by pharmacological inhibition of IL7R downstream effectors.
The knowledge we have generated has a clear impact on the understanding of how IL7 and IL7R promote leukemia, revealing molecular players that act downstream from and/or interplay with IL7/IL7R signaling and constitute promising targets for fine-tuned therapeutic intervention in T-ALL, B-ALL and, potentially, other cancers and conditions that rely on aberrant IL7R-mediated signaling. Moreover, the omics datasets and in vivo models we generated constitute excellent resources to further characterize new players in B- and T-ALL etiology, and to test new therapeutic approaches in immunocompetent, physiologically relevant settings.
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.
The project's ambitious nature implicates it is still difficult to draw definitive conclusions as to the global socio-economic impact it will have, although what we have delivered strongly indicates that the project may have a clear positive impact.
The identification of novel genes involved in IL7R-mediated signaling is a major step forward not only for the thorough characterization of the IL7R signaling networks in health and disease but also for the identification of potential therapeutic vulnerabilities that may be exploited for clinical purposes.
The demonstration that aberrant IL7R signaling can initiate lymphoid leukemia, triggering a set of in vivo events that result in disease development, and that the oncogenic effects of IL7R-mediated signaling are dose-dependent, constitute significant breakthroughs for the understanding of ALL biology that may further have major implications for ALL clinical management and treatment.
We also went beyond the state of the art in generating the first fully-human anti-IL7R for therapeutic purposes (in general, and particularly for T-ALL).
An indication our commitment to translate our findings into outcomes that benefit both science and society is our ERC PoC project IL7RsignaTHER that arose from the current ERC grant, which we hope will lead to future clinical applications.