In some cases, our genes can undergo changes that can make a disease very aggressive. This is the case with a form of Acute Lymphoblastic Leukemia (ALL). How can knowledge of gene alterations lead researchers to select the best medicines, developing effective Precision Medicine protocols?

Leukemias are tumors that originate from blood cells and can develop in either acute or chronic form. They can affect people of all ages, although they’re more frequent found in the elderly. Unfortunately, there is a leukemia called Acute Lymphoblastic Leukemia (ALL) that occurs in both young people and in children. It’s defined as acute because it’s characterized by its increased aggressiveness. In this disease, a blood cell (lymphocyte B or T) undergoes a tumor transformation, which means that the cell begins to reproduce faster; therefore invading the blood, lymph nodes, spleen, liver and central nervous system.

ALL is the most frequently occurring tumor in young people, constituting 80% of leukemias and about 25% of all cancers diagnosed between the ages of 0 and 14 years. The highest incidence occurs between the ages of two and five, and then declines with increasing age.

A study developed in the research laboratories at the Tettamanti Foundation of Monza, in collaboration with the University of Milan Bicocca and other Italian clinical centers, has demonstrated that in a particular form of ALL, the transformation of certain genes is associated with a more severe prognosis.

This research has recently been published in the prestigious international scientific journal Blood and bears the signature of a large group of Italian researchers, led by Dr. Giovanni Cazzaniga and Professor Andrea Biondi.

What did the researchers from the Tettamanti Foundation discover?

As is usually the case in medical research, the study started “long ago”, about 15 years ago, and is based on the analysis (over time) of a significant number of pediatric patients treated at the Centers of the Italian Association of Pediatric Hemato-Oncology (AIEOP or  l’Associazione Italiana di Ematologia e Oncologia Pediatrica).

That there was a genetic basis at the onset of ALL was known; however, the researchers at the Tettamanti Foundation found that in children in whom it’s more difficult to treat leukemia, some genes are fused together, instead of appearing distinct from one-another. This observation was made in 22 of 30 cases followed from 2006 to 2019. In particular, the fusion of one gene, PAX5, was recurrent in 20% of cases and had other genes such as DNAJA1, FBRSL1 and GRHPR as partners.

In these children, disease-free survival at three years was only 25%. That is, children who have ALL and have the fusion between these genes have a lower survival expectancy than those children who don’t have the fusion between the genes.

What are the advantages of this approach?

Having identified the presence of PAX5 gene fused with other genes, in cases of ALL with more difficult prognosis, provides the opportunity of opening new therapeutic possibilities.

That is, to use new experimental drugs that act on PAX5, such as an inhibitor of an enzyme called kinase, which has already demonstrated its antitumor and antiangiogenic effect on several cancers.

In addition, immunotherapy could also be used, particularly in more difficult cases where other genes are also fused together.

Finally, this study shows how important it is to both identify and recognize various genetic subtypes that allow for the modification of therapies, according to the specific risk of disease relapse. It’s also a clear example of the application of Precision Medicine.

What will be the next steps?

This study is still at the level of laboratory research, so the next steps will be substantially directed towards the validation of the clinical protocol, the expansion of the case series, and the submission to regulatory bodies, to make the treatment available in clinical practice.

Below is a short video (in Italian) that summarizes the work of the research group at the Tettamanti Foundation.

This post is also available in: Italiano


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