They identify a new oncogenic and treatable fusion in aggressive hematological tumors

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 T-ALL 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-ALL. Therefore, it is essential to identify the genetic alterations that are present in cancer cells and that promote tumor development, with the aim of developing new personalized therapies that are more effective and have fewer adverse effects.

Now, a study published in the British Journal of Haematology has identified a new fusion gene that promotes tumor development and is sensitive to different pharmacological inhibitors, postulating it as a potential therapeutic target in T-ALL.

The work is the result of translational research carried out by researchers from the Autonomous University of Madrid (UAM), in collaboration with the Hospital Fundación Jiménez Díaz, the National Center for Oncological Research, the Center for Energy, Environmental and Technological Research, the National Epidemiology Center and the Josep Carreras Leukemia Research Institute.

fusion genes

One of the relatively common genetic alterations in T-ALL are 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 a hyperactive 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.

Image: Identification of a new fusion gene in a patient diagnosed with T-ALL. The diagram shows the approach used in this study for the identification of the new SEPTIN6::ABL2 fusion gene in the patient's tumor cells, its characterization as oncogenic, and the identification of specific treatments (Lahera and Vela). The schematic has been created with BioRender.com

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Bibliographic reference:

Lahera, A., Vela-Martín, L., López-Nieva, P., Salgado, RN, Rodríguez-Perales, S., Torres-Ruiz, R., López-Lorenzo, JL, Cornago, J., Llamas, P., Fernández-Navarro, P., Sánchez-Domínguez, R., Segovia, JC, Sastre I., Cobos-Fernández, M.Á., Menéndez, P., Santos, J., Fernández-Piqueras, J. , Villa-Morales, M., 2023 Jun 2 Comprehensive characterization of a novel, oncogenic and targetable SEPTIN6::ABL2 fusion in T-ALL. Br J Haematol . doi: 10.1111/bjh.18901.

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