An international study led by Italy reveals a new molecular mechanism at the origin of a form of leukemia very common in children. The research is coordinated by Italy with the Sapienza University of Rome. The work, published in ‘Oncogene’, opens up new monitoring techniques and new therapies.
Acute lymphoblastic leukemia (ALL) – explain Sapienza – is an aggressive, rapidly evolving hematological tumor that affects T lymphocytes, arresting them in an immature phase. Among acute childhood leukemias, approximately 60% are 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 leukemia cells then infiltrate the bone marrow, causing the disease. Mutations that lead to hyperactivity of the Notch signaling system are found in 60% of patients with T-ALL. Intensive chemotherapy can cure many of the patients, but a high percentage of pediatric and especially adult patients are subject to relapses with an unfavorable prognosis. Notch receptors can in fact contribute to resistance to chemotherapy, making it necessary to find new approaches to counteract its contribution to the progression of T-ALL.
The 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 collaborations with other research institutions – in particular Weill Cornell Medicine of New York for the USA, and in our country also the Italian Institute of Technology (IIT) of Rome, the Azienda Ospedaliera dei Colli Monaldi of Naples, the University of Rome Tor Vergata, the National Cancer Institute Regina Elena Capitolino, the University of Padua and that of Perugia – indicates how the Notch protein modulates the epigenetic mechanisms of regulation of the CXCR4 receptor through interaction with particular microRNAs. Thus it contributes to the blocking of the development and differentiation of T cells, and completely subverts the functions of the thymus, inducing its early involution.
The result – a note explains – was obtained through a transgenic model for the Notch3 gene, which allowed to verify many of the molecular and cellular characteristics of T-ALL, and thanks to the use of multiple advanced techniques of flow cytometry and molecular analysis. The epigenetic data were confirmed through the use of xenograft models obtained using samples of patients affected by T-ALL, transplanted into experimental murine models.
“The work includes, not only among the first names, our young researchers in Italy and abroad – remarks Maria Pia Felli, author of the article – who with professionalism have conducted complex and fundamental experiments for this study, demonstrating passion and enthusiasm for scientific research. The specific expertise provided by each individual author and by the various research centers involved has allowed the realization of this project”.
The results obtained advance scientific knowledge on ALL and suggest these microRNAs as new additional molecular biomarkers for monitoring and, in the future, for advanced therapeutic strategies against the neoplasia.
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