Novel targets modulating the inflammatory response in juvenile myelomonocytic leukemia

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2022 

Juvenile myelomonocytic leukemia (JMML) is a rare cancer of young children, for which there is currently no treatment except hematopoietic stem cell transplant, which succeeds in curing only half of the patients. The biology at the basis of JMML is still unclear, due to its rarity and the lack of appropriate models. There is emerging evidence that cellular mechanisms of stress response are dysregulated in several blood cancers, and in particular in myeloid leukemias. Contrary to what previously thought, persistent inflammation activated by cellular stress can fuel the cancer instead of fighting it. These aspects have not been studied in JMML.
By analyzing gene expression data of JMML patients, we found abnormal expression of genes involved in mechanism of stress response, and, accordingly, signs of abnormal inflammation. We have identified two interesting targets that control an important pathway of cellular stress response. Here, we propose to study the role of these two genes in JMML. To do this, we will first use in vitro models, in which we will experimentally delete or add these genes and study the resulting effect. Next, we will conduct similar studies in a mouse model of JMML, in which we will also use small molecules to pharmacologically modulate stress response pathways.  Finally, we will employ “humanized” mouse models of JMML in which we will transplant patient cells into mice to study the role of the two targets. We think that targeting inflammation and cellular stress response in JMML may represent a valuable therapeutic avenue.