Identification of therapeutic targets in ABL2 fusions-induced oncogenic signaling. Proposal of adjuvant treatments for patients with T-cell lymphoblastic neoplasms.
(IAP-RP-HC25002)

Project members: María Villa Morales (PI), Laura Vela Martín, Isabel Sastre Merlín (UAM); Pilar Llamas Sillero, José Luis López-Lorenzo, Javier Cornago Navascúes, Rocío Salgado Sánchez (IIS-FJD); Concepción Aláez Usón, Sara Nistal Gil (HLA-Moncloa)

Project Summary
T-cell lymphoblastic neoplasms (T-ALL/LBL) are a type of aggressive hematological cancer derived from immature T-cells, mostly affecting children and adolescent boys. Treatment with multiple high-dose chemotherapy has proven to be highly effective, but not infallible, due to acute and long-term toxicity and poor prognosis in case of relapse. With the ultimate goal of implementing personalized and precision medicine and addressing these issues, our team is analyzing molecular-genetic alterations in T-ALL/LBL patients. This allowed us to identify the novel, oncogenic and targetable SEPTIN6::ABL2 fusion, in a T-ALL patient at IIS-FJD who did not overcome the disease with conventional treatment and who, unfortunately, died in 2020. According to the molecular nature of the fusion protein and to the results using cellular models, we suggest that the patient would have benefited from targeted treatment with tyrosine kinase inhibitors (TKIs). However, since such inhibitors may not completely eradicate the corresponding tumor cells, there is a growing need to identify additional pharmacological inhibitors that efficiently block oncogenic signaling triggered by ABL2 alterations, which can be used as second-line treatments or as co-adjuvants together with TKIs to improve the efficiency rates of current therapies.

We have preliminary data indicating that ABL2 alterations, such as SEPTIN6::ABL2 fusion, induce the aberrant activation of a STAT5/PIM1/c-MYC/mTOR axis, followed by an altered gene expression pattern leading to the deregulation of cellular processes relevant to tumor development.

With this project, we aim to identify therapeutic targets within this oncogenic signaling. This information would allow for the proposal of tailored therapeutic strategies for T-ALL/LBL patients with ABL2 alterations like SEPTIN6::ABL2 fusion..