2023-07-05 15:45:10
T-cell acute lymphoblastic leukemia (T-ALL) is a type of aggressive hematological tumor that originates from lymphoblasts committed to the T lineage, which mainly affects the bone marrow and is especially common in children.
Current treatments for acute lymphoblastic cell leukemias achieve reasonable cure rates and consist of high-intensity chemotherapy courses that may be followed by hematopoietic bone marrow transplantation. However, those patients who do not respond to treatment or who relapse have a poor prognosis, with survival rates of less than 10% and few therapeutic options available.
In this regard, since the approval of neralabine in 2005, no new specific drugs have been implemented for the treatment of T-cell acute lymphoblastic leukemia. Therefore, it is essential to identify the genetic alterations that are present in cancer cells and which are the ones that promote tumor development, with the aim of developing new personalized therapies that are more effective and have fewer adverse effects.
Now, a study by a team led by Antonio Lahera and Laura Vela-Martín, both from the Autonomous University of Madrid (UAM) in Spain, has identified a new fusion gene that promotes tumor development and is sensitive to different pharmacological inhibitors, postulating as a potential therapeutic target in T-cell acute lymphoblastic leukemia.
The work is the result of translational research carried out in Spain by researchers from the Autonomous University of Madrid, in collaboration with the Hospital Fundación Jiménez Díaz, the National Center for Oncological Research, the Center for Energy, Environmental and Technological Research, the Center National Institute of Epidemiology and the Josep Carreras Leukemia Research Institute.
Artist’s impression of a cancer cell. (Image: Amazings/NCYT)
fusion genes
One of the relatively common genetic alterations in T-cell acute lymphoblastic leukemia is fusion genes. They consist of a chimera, which is formed by the combination of two different genes. Specifically, the fusion gene that is the object of this study is formed by the SEPTIN6 and ABL2 genes, so it is represented as SEPTIN6::ABL2, since a part of the SEPTIN6 gene constitutes the beginning of the chimera, while a part of the ABL2 gene makes up the end.
In addition, ABL2 is considered a proto-oncogene, that is, a gene whose alteration is likely to promote tumor development and, notably, when it is part of the SEPTIN6::ABL2 fusion, it loses a series of domains that act as negative regulators of its catalytic activity. .
Therefore, in the SEPTIN6::ABL2 fusion, the catalytic activity of ABL2 is constitutively or permanently activated, giving rise to an overactive tyrosine kinase and could promote tumor development.
In this regard, the researchers demonstrate that the SEPTIN6::ABL2 fusion gene induces both the proliferation and survival of different hematopoietic cell models, behaving as an oncogenic fusion gene and contributing to leukemogenesis.
Personalized medicine
Personalized medicine is one of the main lines of action for cancer treatment. It consists of the use of specific drugs against those alterations that are present in cancer cells but not in normal cells, and which are also those that promote tumor development.
Since the SEPTIN6::ABL2 fusion gene meets both premises, it is postulated as a potential therapeutic target for the use of pharmacological inhibitors that act on the aberrant catalytic activity of ABL2.
Specifically, the authors of the study demonstrate that the so-called tyrosine kinase inhibitors selectively and efficiently reverse the tumor development induced by the SEPTIN6::ABL2 fusion gene and, therefore, emerge as a possible treatment for future patients who also present this fusion gene.
The study is titled “Comprehensive characterization of a novel, oncogenic and targetable SEPTIN6::ABL2 fusion in T-ALL”. And it has been published in the academic journal British Journal of Haematology. (Source: UAM)
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