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).
Collaborators: Pablo Menéndez (Josep Carreras Leukaemia Research Institute); Françoise Pflumio (Inserm/CEA/Université Paris); Pablo Fernández Navarro (ISCIII), Pablo Mínguez (IIS-FJD).
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, our team is analyzing molecular-genetic alterations in T-ALL/LBL patients; in a T-ALL patient at IIS-FJD who did not overcome the disease with conventional treatment and who, unfortunately, died in 2020, we have found the novel, oncogenic and targetable SEPTIN6::ABL2 fusion [1]. 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.
With this project, we aim to identify therapeutic targets within the oncogenic signaling pathways induced in T-cell lymphoblastic neoplasms by ABL2 alterations like SEPTIN6::ABL2 fusion. This information would allow to propose tailored therapeutic strategies.
1. Lahera, A., et al., Comprehensive characterization of a novel, oncogenic and targetable SEPTIN6::ABL2 fusion in T-ALL. Br J Haematol, 2023. 202(3): p. 693-698.
The increase during sepsis in the plasma levels of inflammatory cytokines may result in renal proximal tubular cell (PTC) injury, thereby contributing to acute renal injury (AKI) and mortality. Our preliminary results suggest that an increase in intracellular prostaglandin E2 (iPGE2) -triggered by inflammatory cytokines and dependent on the prostaglandin uptake transporter PGT- plays a relevant role in PTC injury. Therefore, PGT inhibitors such as Bromosulfophthalein would protect PTC against the noxious effects of inflammatory cytokines during sepsis.
The present project is aimed to confirm that: Bromosulfophthalein prevents PTC injury sepsis-induced PTC injury (new in vitro model of PTC injury by inflammatory cytokynes and bacterial lipopolysaccharide-LPS) as well as in vivo (LPS murine model of sepsis) and plasmas from septic patients induce PTC injury and that iPGE2 play a relevant role in PTC injury.
The results obtained to date have shown that:
1. Our in vitro model replicates key aspects of AKI, such as cell death, detachment, cytoskeletal disruption, and increased paracellular permeability. These alterations, which impair critically relevant tubular functions are driven by a PGT/iPGE2-dependent mechanism and prevented by Bromosulfophthalein.
2. Our in vitro model also replicates the pro-inflammatory activation of PTC cells during sepsis through i) increasing leukocyte infiltration via upregulation of ICAM-1, VCAM-1, and MCP-1 and ii) secreting factors that induce monocyte chemotaxis, adhesion, and activation into macrophages. Again, these processes rely on a PGT/iPGE2-dependent mechanism and prevented by Bromosulfophthalein.
3. Plasma from patients with sepsis-induced AKI contains soluble factors that, through a PGT/iPGE2-dependent, Bromosulfophthalein-sensible mechanism, cause cell death, reduced proliferation, increased permeability, and pro-inflammatory activation in HK-2 cells.
Based on these results, which confirm the hypothesis and the objectives outlined above, it remains to be confirmed that Bromosulfophthalein also prevents sepsis-induced AKI in an in vivo model.
