Acute lymphoblastic leukaemia (ALL) is a rapidly evolving aggressive haematological tumour that affects T lymphocytes by arresting them in an immature phase. Among childhood acute leukaemias, about 60 % is represented by ALL. Genetic abnormalities block the differentiation of T-cell precursors in the thymus, a gland located in the mediastinum, in front of the heart, and promote abnormal cell proliferation. The accumulating leukaemic cells then infiltrate the bone marrow causing the disease.

Mutations leading to hyperactivity of the Notch signalling system are found in 60% of T-ALL patients. Intensive chemotherapy can cure many of the patients, but a high percentage of paediatric and especially adult patients then relapse with a poor prognosis. Notch receptors may contribute to chemotherapy resistance, making it necessary to search for new approaches to counteract its impact on T- ALL progression.

A new study, conducted by the Department of Experimental Medicine of Sapienza in collaboration with the Department of Molecular Medicine, and the result of a network of partnerships with other research institutions, offers important advances in understanding the tumour mechanism. The research results, recently published in the journal Oncogene, showed how the Notch protein modulates the epigenetic regulatory mechanisms of the CXCR4 receptor through interaction with particular microRNAs. In this way, it contributes to the blockage of T-cell development and differentiation and completely subverts the functions of the thymus by inducing its early involution.

This was achieved using a transgenic model for the Notch3 gene, which made it possible to verify many of the molecular and cellular features of T-ALL, and through the use of multiple advanced cytofluorimetry and molecular analysis techniques. Epigenetic data were confirmed by using xenograft models obtained using samples from T-ALL patients transplanted into experimental mouse models.

"The work includes, not only among the first names, our young researchers in Italy and abroad, who have professionally carried out complex experiments that are fundamental to this study, demonstrating passion and enthusiasm for scientific research. The specific expertise provided by each author and the various research centres involved enabled this project to be realised" says Maria Pia Felli, author of the article. In particular, in addition to Sapienza University, the Weill Cornell Medicine in New York, the Italian Institute of Technology (IIT) in Rome, the Azienda Ospedaliera dei Colli Monaldi in Naples, the University of Rome Tor Vergata, the Istituto Nazionale Tumori Regina Elena in Rome, the University of Padua and the University of Perugia took part.

The findings advance scientific knowledge on this type of tumour and suggest these microRNAs as additional new molecular biomarkers for monitoring and, in the future, for advanced therapeutic strategies against this disease.

References:

Notch3-regulated microRNAs impair CXCR4-dependent maturation of thymocytes allowing maintenance and progression of T-ALL – Ilaria Sergio, Claudia Varricchio, Sandesh Kumar Patel, Martina Del Gaizo, Eleonora Russo, Andrea Orlando, Giovanna Peruzzi, Francesca Ferrandino, Georgia Tsaouli, Sonia Coni, Daniele Peluso, Zein Mersini Besharat, Federica Campolo, Mary Anna Venneri, Donatella Del Bufalo, Silvia Lai, Stefano Indraccolo, Sonia Minuzzo, Roberta La Starza, Giovanni Bernardini, Isabella Screpanti, Antonio Francesco Campese, Maria Pia Felli

Oncogene - DOI: 10.1038/s41388-024-03079-0

Further Information

Maria Pia Felli

Department of Experimental Medicine, Sapienza Università di Roma

mariapia.felli@uniroma1.it