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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - IL7sigNETure (IL-7/IL-7R signaling networks in health and malignancy)

Teaser

Summary

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 showed that patients with T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematological cancer, 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 remains limited. Here, we propose to move from the single molecule/pathway-centered analysis that has characterized the research on IL7/IL7R signaling, into a global view of the IL7/IL7R signaling landscape and its in vivo pathophysiological impact. The knowledge we will generate should have a profound impact on the understanding of the fundamental mechanisms by which IL7 and IL7R promote leukemia and reveal novel targets for fine-tuned therapeutic intervention in T-ALL and, potentially, other cancers.

Work performed

The work has moved forward as planned: we moved forward with all the proposed in vitro and in vivo tasks. Concerning Aim 1, we have performed the primary and secondary chemical screens to identify small molecules that modulate IL-7/IL-7R signaling, transcriptomics and proteomics are underway. Regarding Aim 2, we are characterizing the different animal models we generated, with important findings on the impact of aberrant IL7R signaling in T-ALL and its interactions with other oncogenes. Our efforts to validate anti-IL7/IL-7R signaling therapeutic agents against T-ALL have also started leading to positive outcomes that we expect should result in scientific deliverables soon.

Final results

The project\'s ambitious nature implicates it is still at a stage of execution that does not allow us to draw definitive conclusions as to the actual socio-economic impact it will have. On the other hand, our current data provide strong support to our initial expectations that the project will lead to the generation of significant insights into the biology of leukemia that will go significantly beyond the state of the art and therapeutic tools that will be innovative and with clinical potential, some of which we are preclinically testing already.