Potential therapeutic target against aggressive hematological tumors

Recent research has made it possible to discover that deregulation of the SOCS3 gene contributes to the activation of a cell signaling pathway in aggressive hematological tumors.

The authors of this study, including Antonio Lahera and Pilar López-Nieva, both from the Autonomous University of Madrid (UAM) in Spain, have identified hypermethylation (epigenetic alteration) of the SOCS3 gene as a frequent event in tumors. aggressive hematologic tumors known as “precursor T-cell neoplasms.”

The results also show that a lower expression of SOCS3 contributes to the constitutive activation of the JAK/STAT cell signaling pathway through different mechanisms, such as an increase in the oncogenic potential of some mutations.

In summary, these findings reveal the importance of deregulation of the SOCS3 gene for the constitutive activation of the JAK/STAT pathway, proposing SOCS3 as a potential therapeutic target in precursor T cell neoplasms.

Precursor T cell neoplasms

Precursor T-cell neoplasms are aggressive hematologic tumors that arise from lymphoblasts committed to the T-cell lineage. These neoplasms predominantly affect the bone marrow and blood, in which case they are called T-cell acute lymphoblastic leukemia (T-cell). -ALL); although, less frequently, they can also appear as a tumor mass in the thymus/anterior mediastinum or in the lymph nodes, and in this case they are called T-cell lymphoblastic lymphoma.

Although current treatments for precursor T-cell neoplasms achieve a reasonable cure rate, their associated high toxicity and poor prognosis in case of relapse (with survival rates of less than 10%) highlight the need to develop new personalized therapies that are more effective and have fewer side effects.

JAK/STAT is a cell signaling pathway that is frequently deregulated in precursor T cell neoplasms, since it is constitutively or permanently activated and, as a result, promotes tumor development.

However, to date, no personalized therapy has been approved for patients diagnosed with precursor T-cell neoplasms that present constitutive activation of the JAK/STAT pathway. Therefore, it is essential to delve into the molecular alterations that contribute to the constitutive activation of the JAK/STAT pathway and that are present in these patients, with the aim of identifying new therapeutic targets.

Artist’s impression of a cancer cell. (Illustration: Amazings/NCYT)

hypermethylation

The authors of the new study examined epigenetic alterations in the SOCS3 gene; that is, alterations that do not produce a change in the nucleotide sequence of the gene but are capable of modifying its expression levels.

Specifically, they studied DNA methylation, a type of epigenetic alteration that consists of the addition of methyl groups to the cytokines that form part of the so-called dCpG dinucleotides. All with the aim of evaluating whether aberrant DNA methylation could contribute to the constitutive activation of the JAK/STAT pathway in precursor T cell neoplasms.

“When the methylation process affects the region of the gene where the regulatory sequences necessary for the initiation of transcription are located,” the researchers explain, “it results in a decrease in the expression levels of the gene in question, since it is difficult to access to the machinery responsible for DNA transcription.

“This phenomenon of hypermethylation has been reported recurrently in tumor cells, where it affects what are known as tumor suppressor genes, that is, those genes that inhibit tumor development.”

“In this way -the authors conclude-, an aberrant methylation in tumor suppressor genes would reduce their expression levels and, therefore, would favor the viability and proliferation of tumor cells”.

These results have been the result of translational research (basic research applied to the early stages of drug development) carried out by the UAM and the Fundación Jiménez Díaz University Hospital, with the participation of the Carlos III Health Institute and the Oncology Institute. of Asturias, in Spain.

The study is titled “SOCS3 deregulation contributes to aberrant activation of the JAK/STAT pathway in precursor T-cell neoplasms”. And it has been published in the academic journal British Journal of Haematology. (Source: UAM)